It is now known that a large majority of benign gastric and duodenal ulceration is due to H. pylori infection (following Marshall and Warren’s Nobel prize-winning experiments ¹^,²); most of the remainder can be attributed to NSAID use. Colonisation of the stomach with H. pylori is seen in virtually all patients with a duodenal ulcer and in 70–80% of those with gastric ulcers. H. pylori appears to stimulate increased acid secretion. All patients colonised with H. pylori develop gastritis, but only about 20% have ulcers or other lesions. As yet incompletely understood host factors and differences in strain of the organism are likely to explain this discrepancy.

H. pylori infection is carcinogenic and is the leading cause of gastric carcinoma. It is also highly associated with gastric MALT lymphoma. Eradication of the organism can lead to regression and even resolution of this latter malignancy.

Somewhat counterintuitively, H. pylori infection is not a cause of acid reflux disease, and in fact its eradication may precipitate or exacerbate acid reflux. Indeed, the recent surge in oeosphageal adenocarcinoma incidence in the West has been blamed by many on the now commonplace practice of searching for and eradicating H. pylori, although this has conversely resulted in a fall in the incidence of gastric cancer.

NSAIDs: enemies of the gut

Some 500 million prescriptions for NSAIDs are written each year in the UK, and 10–15% of patients develop dyspepsia while taking these drugs. Gastric erosions develop in up to 80%, but these are usually self-limiting. Gastric or duodenal ulcers occur in 1–5%. The incidence increases sharply with age in those over 60 years, and the risk of ulcers and their complications is doubled in patients aged more than 75 years and those with cardiac failure or a history of peptic ulceration or bleeding. All NSAIDs are ulcerogenic, but ibuprofen is less prone to cause these problems than other non-selective NSAIDs.

NSAIDs are weak organic acids and the acid milieu of the stomach facilitates their non-ionic diffusion into gastric mucosal cells. Here the neutral intracellular pH causes the drugs to become ionised and trapped in the mucosa because they cannot diffuse out in this form.

Aspirin and the other NSAIDs inhibit cyclo-oxygenase (COX) (see Ch. 16). In the stomach, the constitutively expressed COX-1 isoform is responsible for the production of the gastroprotective prostaglandins E2 and I2 (see above). Inhibition of the inducible COX-2 isoform (which is normally up-regulated in activated inflammatory cells) is responsible for NSAIDs’ anti-inflammatory properties. Most NSAIDs inhibit both isoforms unselectively, so the beneficial anti-inflammatory effect is offset by the potential for mucosal injury by depletion of protective prostaglandins. Aspirin is particularly potent in this respect, perhaps because it inhibits COX irreversibly, unlike the other NSAIDs where inhibition is reversible and concentration dependent.

Selective COX-2 inhibitors represent an attempt to provide beneficial anti-inflammatory effects without promoting ulceration. Unfortunately, there is evidence that unopposed COX-2 inhibition results in an increased risk of thrombotic events (including myocardial infarction and stroke); the UK Committee on Safety of Medicines therefore counsels against their use in preference to non-selective NSAIDs in the absence of a compelling indication, and cardiovascular risk should be assessed.

Drugs affecting oesophageal motility and the lower oesophageal sphincter

The D₂ agonist drugs domperidone and metoclopramide (see below) can have a beneficial effect on reflux symptoms, firstly by enhancing gastric emptying and thus reducing the volume of acid available to reflux up the oesophagus, and secondly by increasing lower oesophageal sphincter (LOS) basal tone.

A number of drugs reduce tonic lower oesophageal sphincter tone or increase transient lower oesophageal sphincter relaxation and thus promote reflux, including nitrates, theophyllines, drugs with antimuscarinic activity or unwanted effects, and calcium channel antagonists. The pharmacology and pharmocokinetics of these drugs appear in detail elsewhere (see Index). These agents may occasionally be useful in alleviating the symptoms of oesophageal spasm, although the effect is usually disappointing. They are rarely potent enough to be of significant use in achalasia. Commonly used examples include nifedipine, diltiazem, and modified-release nitrates.

Newer therapies being explored in the treatment of GORD include GABA inhibition to reduce transient lower oesophageal sphincter relaxations. Baclofen (see p. 304) is clinically effective but has limiting CNS unwanted effects, and more tolerable compounds are being investigated. Other pharmacological targets which are showing potential in early clinical research include cannabinoid agonists.

Drugs to reduce or neutralise gastric acid

Proton pump inhibitors (PPIs)

Pharmacology

As can be deduced from the above, the most effective site of action for antisecretory drugs is the proton pump. Proton pump inhibitors are taken up by parietal cells from the portal circulation and are then excreted into the acid milieu around the secretory canaliculus. The resulting ionised form binds irreversibly to the proton pump, resulting in virtual total inhibition of acid secretion (Fig 32.1).

Fig. 32.1 Secretion of acid by the parietal cell.

Pharmacokinetics

PPIs are available in oral and intravenous formulations. Oral PPIs are degraded at low pH and must be given in enteric-coated forms. Systemic availability increases with dose and also with time, owing to decreased inactivation of the prodrug as gastric acidity is reduced. Maximum efficacy occurs after up to 5 days of therapy. Uninhibited Na⁺/K⁺-ATPase will regenerate when the PPI is discontinued; this may take 2–3 days

Adverse reactions and interactions

PPIs are as a rule well tolerated and serious adverse effects are unusual. Given their mechanism of action, there are theoretical concerns about cancer (due to the stimulatory effect of the hypergastrinaemia resulting from the loss of negative feedback), mineral deficiencies (due to loss of acid-related absorption of iron, calcium and B₁₂, for example) and enteric infections (due to the loss of the antibacterial properties of a strongly acidic environment). Although an increased incidence of osteoporotic fractures and Clostridium difficile (C. diff) colitis has been noted in some observational studies, there has been no good evidence that these risks are significant, even after almost 20 years of clinical experience.

Examples of PPIs are omeprazole (10–20 mg daily), lansoprazole (15–30 mg daily) and pantoprazole. All are similar in pharmacokinetics, efficacy and adverse effect profile.

H₂ receptor antagonists (H₂RAs)

Pharmacology

H₂RAs are less potent than the PPIs, as alternative pathways of parietal cell activation remain uninhibited. They competitively inhibit histamine binding at H₂ receptors on the basolateral aspect of parietal cells, resulting in a reduction of gastric acid secretion. The inhibitory effect can be overcome with high gastrin levels, as occurs postprandially. Tolerance may develop, probably due to down-regulation of receptors.

Pharmacokinetics and dosage

H₂RAs are given orally and are well absorbed. Since there is anecdotal evidence that peptic ulcer healing with H₂-receptor antagonists correlates best with suppression of nocturnal acid secretion, many prefer to give these drugs as a single evening dose (e.g. ranitidine 150–300 mg).

Adverse effects and interactions

H₂RAs are generally well tolerated. Adverse effects and interactions are few with short-term use. Cimetidine is a weak anti-androgen, and may cause gynaecomastia and sexual dysfunction in males. Cimetidine inhibits cytochromes P450 and there is potential for increased effect from any drug with a low therapeutic index that is inactivated by these isoenzymes, e.g. warfarin, phenytoin. Ranitidine and famotidine avoid these unwanted effects.

H₂RAs are available as over-the-counter preparations in the UK, albeit of lower strength than those available on prescription. A potential danger is that patients with serious pathology such as gastric carcinoma will self-medicate, allowing their disease to progress. Pharmacists are trained to advise patients to consult their doctor if they have recurrent symptoms or other worrying manifestations such as weight loss.

Antacids

Antacids directly neutralise secreted acid and raise intragastric pH. They protect the gastric mucosa against acid (by neutralisation) and pepsin (which is inactive above pH 5, and which in addition is inactivated by aluminium and magnesium). Most commonly they are magnesium or aluminium salts. The hydroxide is the most common base, but trisilicate, carbonate and bicarbonate are also used.

Antacids relieve mild dyspeptic symptoms and they are taken intermittently when symptoms occur. Unwanted effects and inconvenience (see below) limit their regular use.

Individual antacids

Numerous antacid preparations are available over the counter. Some of the more common are described here.

Sodium bicarbonate reacts with acid and relieves pain within minutes. It is absorbed and causes a metabolic alkalosis. This is not of clinical significance if used on an intermittent, short-term basis but if given regularly over a period of time (days to weeks or longer) or in large doses will result in a potentially dangerous metabolic alkalosis. Sodium bicarbonate can release sufficient carbon dioxide in the stomach to cause discomfort and belching, which may have a beneficial psychotherapeutic effect.

Magnesium oxide and hydroxide react quickly, and magnesium trisilicate more slowly with gastric hydrochloric acid. All magnesium salts cause an osmotic diarrhoea.

Aluminium hydroxide reacts with hydrochloric acid to form aluminium chloride; this in turn reacts with intestinal secretions to produce insoluble salts, especially phosphate. It tends to constipate.

Some antacid mixtures contain sodium, which may not be readily apparent from the name of the preparation and thus may be dangerous for patients with cardiac, renal or liver disease. For example, a 10-mL dose of magnesium carbonate mixture or of magnesium trisilicate mixture contains about 6 mmol sodium (normal daily dietary intake is approximately 120 mmol sodium).

Aluminium– and magnesium-containing antacids may interfere with the absorption of other drugs by binding with them or by altering gastrointestinal pH or transit time. It is probably advisable not to co-administer antacids with drugs that are intended for systemic effect by the oral route.

Other targets for acid suppression

Gastrin inhibitors exist as experimental tools only as they are not effective acid suppressants. Antimuscarinic treatments for peptic ulceration are obsolete, but underlie the rationale for the surgical vagotomy which is now rarely performed.

Drugs to enhance mucosal protection

Sucralfate (SUCRose sulFATE and ALuminium hydroxide complex)

Sucralfate provides a physical barrier to gastric acid. It is activated by acid to produce a viscous gel, and will therefore be ineffective if given with therapies that inhibit acid release or raise gastric pH. In the acid environment of the stomach, the aluminium moiety is released so that the compound develops a strong negative charge and binds to positively charged protein molecules that transude from damaged mucosa. The result is a viscous paste that adheres selectively and protectively to the ulcer base. It also binds to and inactivates pepsin and bile acids, which has the added benefit of reducing mucus degradation. Its therapeutic efficacy in healing gastric and duodenal ulcers is approximately equal to that of the histamine H₂-receptor antagonists.

Adverse effects and interactions

Sucralfate may cause constipation but is otherwise well tolerated. The concentration of aluminium in the plasma may be raised but this appears to be a problem only with long-term use by uraemic patients, especially those undergoing chronic intermittent haemodialysis. As the sucralfate is effective only in acid conditions, an antacid should not be taken 30 min before or after a dose. Sucralfate interferes with absorption of several drugs, including ciprofloxacin, theophylline, digoxin, phenytoin and amitriptyline, possibly by binding due to its strong negative charge.

Bismuth chelate (tripotassium dicitratobismuthate, bismuth sub-citrate)

This substance was thought to act by chelating with protein in the ulcer base to form a protective coating against adverse influences of acid, pepsin and bile. It may also promote protective prostaglandin, mucus and bicarbonate synthesis. Probably more importantly, bismuth chelate is now known to suppress Helicobacter pylori growth, especially when combined with an antimicrobial (see below). Bismuth chelate finds use for benign gastric and duodenal ulcer, and has a therapeutic efficacy approximately equivalent to that of histamine H₂-receptor antagonists. Ulcers remain healed for a longer time after bismuth chelate than after H₂-receptor antagonists, probably due to its ability to eradicate H. pylori.

Adverse effects

Bismuth chelate, particularly as a liquid formulation, darkens the tongue, teeth and stool; the effect is less likely with the tablet, which is thus more acceptable. Systemic absorption of bismuth from the chelated preparation is small but it does pass into the urine and it is prudent to avoid the drug for patients with impaired renal function. Urinary elimination continues for months after bismuth is discontinued. Bismuth toxicity causes encephalopathy.

Misoprostol

Misoprostol is a synthetic analogue of the protective prostaglandin E1 and therefore has the same antisecretory and cytoprotective properties. Traditionally it has been co-administered with NSAIDs to counteract the latter’s effects on endogenous prostaglandin synthesis.

Adverse effects

Diarrhoea and abdominal pain, transient and dose related, are the commonest. Women may experience gynaecological disturbances such as vaginal spotting and dysmenorrhoea; the drug is contraindicated in pregnancy or for women planning to become pregnant, as the products of conception may be aborted. Indeed, women have resorted to using misoprostol (illicitly) as an abortifacient in parts of the world where provision of contraceptive services is poor.

Alginate

Alginate is a common and harmless component of antacids. It forms a viscous raft which forms a physical barrier between the gastric contents and the oesophageal, gastric and duodenal mucosa.

Pharmacological management

Gastro-oesophageal reflux

Lifestyle modification includes reduction in habits that promote acid reflux. Caffeine, alcohol, smoking and obesity relax the lower oesophageal sphincter and should be substituted or discontinued if possible. Avoid late evening meals to allow time for the stomach to empty before lying supine. Minor occasional symptoms are effectively managed with over-the-counter alginate-containing antacids.

The mainstay of medical treatment of acid reflux disease is the neutralisation or reduction of gastric acid production, and is therefore most easily achieved with PPIs, although H₂RAs (e.g. ranitidine 150–300 mg daily) may be sufficient. Endoscopically proven oesophagitis may require 4–6 weeks of PPI therapy to heal (e.g. omeprazole 20 mg once daily; lansoprazole 30 mg once daily). If symptoms recur, the lowest effective antacid dose should be used to maintain remission. Doses may need to be doubled in severe or refractory cases. Prokinetic drugs such as domperidone 10–20 mg four times daily or metoclopramide 10 mg three times daily can improve symptoms, best in conjunction with an antisecretory agent.

Reflux-like symptoms unresponsive to PPI therapy are unlikely to be due to acid reflux and alternative causes require exploration. Biliary reflux can produce identical symptoms to acid reflux, and is unresponsive to PPI therapy due to its alkaline nature. It may respond to prokinetic therapy.

Eosinophilic oesophagitis

This is increasingly recognised as an important cause of oesophageal symptoms. It is a disorder of unknown aetiology characterised by substantial eosinophilic submucosal infiltrates in the absence of significant acid reflux and may be associated with other atopic conditions. Treatment options are limited, but topically applied corticosteroids (e.g. swallowing inhaled steroids) can be helpful in inducing and maintaining remission.

Oesophageal dysmotility

This can be notoriously difficult to treat satisfactorily. Prokinetic drugs can be tried in cases of confirmed oesophageal hypomotility; conversely, a calcium channel antagonist or a long-acting nitrate can be tried if the problem is predominantly one of spasm. Treatment of coexistent reflux may improve spasm secondary to reflux.

Pharmacological management of achalasia ³ is best viewed as a temporary measure and drugs which reduce LOS tone rarely provide effective symptomatic improvement. Botulinum toxin, which inhibits cholinergic transmission by reducing ACh release from pre-synaptic motor neurones (see Ch. 22), can be injected endoscopically into the LOS and results in medium-term (3–6 months) relaxation of the LOS and symptomatic improvement. Endoscopic dilatation or surgical correction results in longer-term improvement. Relaxation of the LOS results in potentially free reflux of gastric acid contents and must therefore be accompanied by a PPI.