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Castle Hill Hospital
Gastro-oesophageal reflux disease (GORD) is a common medical problem. Its predominant symptom is heartburn, and it is estimated that 20–40% of the adult population experience heartburn, with daily symptoms occurring in approximately 7% of adults.(1) These symptoms can significantly reduce the quality of life of sufferers. Prolonged untreated disease may result in the formation of strictures and metaplasia of oesophageal mucosa, leading to Barrett’s oesophagus. Other complications include oesophageal ulceration, bleeding and anaemia. Furthermore, GORD is associated with asthma, laryngitis, nocturnal coughing and dental problems.
Physicians generally divide GORD into two categories, based on endoscopic findings. These are referred to as erosive (presence of breaks in the mucosa, such as oesophagitis and ulceration) and nonerosive (also referred to as endoscopy-negative) disease.
The aim of therapy is primarily to alleviate symptoms, and secondarily to prevent complications. In erosive disease, there is an additional therapeutic target of healing oesophagitis and ulceration. This article discusses the drugs used in the treatment of GORD.
A lax gastroesophageal sphincter allowing the reflux of gastric contents is the main cause of GORD. This may be due to anatomical displacement, such as a hiatus hernia, or diaphragmatic laxity due to obesity. However, this view is rather simplistic. Studies have shown that patients with GORD also have poor oesophageal clearance and poor gastric emptying and, hence, delayed acid clearance and increased contact time between gastric contents and the oesophageal mucosa.
There are also wide variations in symptoms perception between different patients. Studies show that, for the same acid challenge, some individuals perceive symptoms while others do not, and that patients may have normal oesophageal pH profile while complaining of reflux symptoms.
For many patients, GORD is a consequence of lifestyle behaviour. Alcohol, smoking and consumption of coffee and chocolate are all potent triggers of gastroesophageal sphincter relaxation. Late meals and alcohol before going to bed is just asking for the inevitable. However, attempts to persuade patients to alter their lifestyle (eg, weight loss or alcohol/smoking cessation) often fail.
Antacids and alginates
Simple antacids are effective for many reflux sufferers with occasional symptoms. Alginate-containing products form a raft that acts as a barrier to gastric contents. Most of these products have over-the-counter (OTC) licences and are convenient for the patient.
H(2)-receptor antagonists were the first important drugs to reduce gastric acid secretion. They are a remarkably successful class of drugs for the treatment of other acid-related conditions such as gastric and duodenal ulcers before the advent of Helicobacter pylori eradication. Ranitidine, cimetidine, famotidine and nizatidine are available and licensed for the treatment of reflux oesophagitis, usually at a higher dose twice daily. However, these drugs produced healing rates of only 47–72% after eight weeks and have now been largely superseded by proton pump inhibitors (PPIs). They may still offer relief of symptoms to patients with milder or nonerosive disease. Some products are available OTC at reduced dosages (eg, ranitidine 75mg, famotidine 10mg). OTC availability is also helpful for patients who wish to self-medicate.
Motility stimulants have only a minor role in GORD. Metoclopramide and domperidone can promote gastric emptying and increase oesophageal sphincter pressure. However, these drugs are in fact weak agents, and they may be used as adjunct to antisecretory treatment. Cisapride held promise as a prokinetic, but the drug was withdrawn because it can induce cardiac arrhythmias.
PPIs are the mainstay in the treatment of GORD. They are highly effective in the treatment of erosive oesophagitis and the relief of symptoms. Trials have demonstrated mucosal healing rates of over 90% with PPIs.
At present, there are five available products on the market. Omeprazole, the longest-established product, is off-patent in many European countries and is therefore cheaper than the other products. The other PPIs are lansoprazole, rabeprazole, pantoprazole and esomeprazole. Esomeprazole is the S-isomer of omeprazole.
The relative potencies of the products differ, and there are also minor differences in pharmacokinetics, but their clinical significance is disputed. The primary mode of drug elimination is via the hepatic CYP2C19 enzyme for omeprazole, lansoprazole and pantoprazole. The exact mode of hepatic clearance of rabeprazole is not fully elucidated. The activity of the CYP2C19 enzyme is subject to genetic variability. Individuals who are homozygous to the mutant (defective) gene are poor at clearing the drug and thus achieve higher drug levels at the same dose. However, this defective gene is present in only 3–6% of European populations, although it may occur in as many as 22.5% of Asian populations. In clinical practice, the significance of pharmacogenetic variability is minor.
Other drugs, such as theophyline and warfarin, which are metabolised by the P450 system, may cause drug interactions, although they are rarely clinically significant.
The principal adverse reactions observed with these drugs are headaches, rashes and diarrhoea. Drug switching may be helpful, but some individuals may be poorly tolerant of all PPIs.
Tailoring treatment to patient requirements
Patients with erosive oesophagitis require healing doses of PPI. The therapeutic aim is mucosal healing and prevention of complications such as bleeding and stricture formation. Since the introduction of these drugs, peptic oesophageal strictures have reduced in incidence in developed nations. Recurrence after cessation of therapy is common, and maintenance treatment is necessary in over 50% of cases. Long-term studies of up to five years have shown that maintenance doses of PPIs can keep patients symptom-free in nearly 90% of cases.92) Although there is no trial evidence, it is usually recommended that patients with Barrett’s oesophagus are kept on maintenance therapy.
In patients with nonerosive disease, the therapeutic goal is symptom-free status. Here, the minimum therapy required to keep patients satisfied should suffice. Antacids and H(2)-antagonists progressing to low-dose PPIs may be tried. Self-medication or “on-demand” therapy, which gives patients control over their symptoms, is popular. A recent study of on-demand therapy versus continuous therapy with leading PPIs showed that patients preferred on-demand therapy and that they dosed themselves on average once every three days.(3)
If drug treatment fails
A small number of patients are intolerant of PPIs or do not wish to take drugs. Surgical and endoscopic treatments are available. Surgery may also be the only recourse for patients with persistent regurgitation of gastric contents that cannot be improved with PPI therapy (volume refluxers). Surgery is now usually carried out laparoscopically and involves a plication (stitching) of a wrap of gastric fundus. Recent advances in endoscopic methods are beginning to gain wider acceptance. A variety of methods are available, including endoscopic stitching devices and injection of bulking agents into the lower end of the oesophagus. Their role is yet to be fully evaluated.
When drugs fail, it is often because the symptoms have a strong associated functional or motility disorder rather than acid reflux alone.