Esomeprazole for the Treatment of Gastroesophageal Reflux disease
Gastric acid has been known for many decades to be a key component in normal upper gastrointestinal functions as it plays a vital role in protein digestion and calcium and iron absorption, as well as protection against bacterial infections. However higher levels of this corrosive liquid can lead to several widespread pathological conditions, for instance, Gastroesophageal reflux disease or Peptic ulcers. (1) Gastroesophageal reflux disease, also known as acid reflux disease is a condition in which the liquid content of the stomach backs up, or refluxes, into the oesophagus. This liquid usually contains pepsin, which is an enzyme that breaks down protein in the stomach, bile juice and stomach acid. A band of muscle at the lower part of the oesophagus, known as lower oesophageal sphincter (LES), acts as a barrier to prevent the reflux of stomach contents into the oesophagus. Gastroesophageal reflux occurs when the LES barrier is relaxed at inappropriate times, is weak, or is somehow compromised. (2) Occasional reflux occurs normally, and without consequence, other than occasional heartburn, in people who do not have GERD but people with GERD, reflux causes frequent symptoms and damages the lining of the oesophagus (2). The other symptoms that patient faces include chest pain, difficulty swallow and sensation of a lump in their throat.
Millions of people around the world suffer from Gastroesophageal reflux disease (GERD) each year. It is stated that in 1988, more than 61 million American adults said they suffer from it at least once a month. The Gastroesophageal disease was thought to be a disease affecting white males over 50. (2) However, that no longer holds true as acid reflux affects every race, gender and adult age group and if it is left untreated, or insufficiently treated, it can lead to severe inflammation in the oesophagus, stomach, lungs, vocal cords, and throat. In the worst case scenario, it can also progress to oesophageal cancer which is the fastest growing cancer in America and Europe since the mid-1970s. (3)
Thirty years ago, GERD could have been threatening if left untreated. Options for treatment at that time were limited. For example, an antacid was administered to neutralize excess stomach acid, which promotes ulcer formation, prevent healing and only provided temporary relief. The other options involved surgery, which causes some serious side effects. The medical treatment for the acid-related disease had a breakthrough after the introduction of histamine 2 antagonist and later proton pump inhibitors (PPI). Omeprazole is the first PPI that was used in clinical practice. We tested hundreds of compounds chemically based on Omeprazole in order to find discover a new PPI with the properties superior to omeprazole and that is how esomeprazole is discovered.
Patients likely to benefit esomeprazole are those who are newly diagnosed from GERD as combination therapy along with other PPI. For the long-term (4 to 8 weeks or longer) relief of pain and healing and certain ulcer, PPI are more effective than H2 antagonist as standard PPI doses block more than 90 % of stomach acid secretion versus 50 to 80% blockade that can seem in H2 antagonist (6). The recent clinical guideline recommends treatment with PPI as an initial therapy for a patient with symptoms impacting with their quality of life, while the H2 antagonist is recommended for a patient whose symptoms are mild and infrequent.
In the current market, there exists a demand for a therapy with better treatment of GERD as its worldwide incidence and associated complications are increasing alongside the exponentially increasing problem of obesity. GERD is one of the most frequent diseases in the western world, with a prevalence of 10% to 20%. In epidemiological trials it has been shown that heartburn occurs at least once per month in 30% -40% of all adults, at least once per week in 10% to 20% of all adults and daily in 4% to 10% of all adults in the western countries. (6)
The table below shows a review of study result regarding prevalence estimates in the world
A review study published in the journal Gut reports the following range of GERD prevalence estimates in global populations
North America 18-28%
East Asia 3-8%
The Middle East 9-33%
South America 23%
For many patients, acid regurgitation and heartburn can severely affect their quality of life. Night-time heartburn can also cause sleeping difficulties, chronic cough, laryngitis, new or worsening asthma and impair next-day function. An improvement in the quality of life by providing effective treatment of the symptoms is, therefore, the prime therapeutic goal for the treatment of acid reflux disease. Clinical studies with GERD patients showed that an appropriate inhibition of the acid secretion resulted in an effective reduction of symptoms.
The cost of the esomeprazole is beyond comparison to the benefit it provides to the patient in need to well manage GERD and have better a quality of life. Since GERD is a chronic disease instead of an acute illness, it causes significant financial impact due to the expense of the long-term management of the disease. The direct expense associated with the disease include costs of prescription medications and over-the-counter, hospital and physician office visits, surgical costs and costs of possible complications, such as Barrett’s oesophagus and oesophageal adenocarcinoma, that may result from the disease. Perhaps the most significant cost associated with a chronic condition such as GERD are the indirect expenses of the disease. Decreased work productivity and time off work, as well as a decrease in the quality of life of patients, are the indirect expenses which are associated with GERD. According to a recent study on the burden of chronic gastrointestinal disorders, GERD was found to be the most expensive, with direct and indirect costs totalling $10 billion per year.
The advantage of using esomeprazole is that patient will to better manage their condition which will lead to less emergency visit, therefore less expenditure on the NHS and health insurance companies. Therefore, in the long term, they will help save money as well as increase patient quality of life. The healthcare system will see that it is worth investing money on esomeprazole and gaining effective treatment of their patient instead of spending money on the currently available therapies or treatment that does not meet the needs or result in better management of GERD.
A stepwise approach is taken for the treatment of GERD in which the primary goals are to control symptoms, to heal esophagitis, to prevent recurrent esophagitis and other complications. The treatment includes lifestyle modifications and control of gastric acid secretion through medical therapy with antacids or proton pump inhibitors or surgical treatment with corrective antireflux surgery. (4)
Esomeprazole’s pharmacological activity of gastric acid secretion is based on inhibition of the proton pump. Esomeprazole belongs to the class known as Proton pump inhibitor (PPI) that suppresses gastric acid secretion by specific inhibition of the H+/K+ -ATPase in the gastric parietal cell. By acting specifically on the proton pump, esomeprazole blocks the last phase in acid production, thus reducing gastric acidity. The S- and R-isomers of omeprazole are protonated and transformed in the acidic compartment of the parietal cell forming the active inhibitor. (7) This effect is based on the dose, up to daily dose of 20 to 40 mg. Esomeprazole not only reduces acid production but can also use to promote healing of erosive esophagitis resulted by stomach acid.
The pharmacokinetic properties of esomeprazole have been studied in the patients suffering from GERD which shows that it is rapidly absorbed and the extent of absorption is higher resulting in higher systemic bioavailability, which combined with reduced clearance results in greater systemic exposure. The absolute bioavailability is 64% after single dose administration of 40mg and increases to 89% after repeated once daily administration whereas for 20mg esomeprazole the corresponding values are 50% and 68%, respectively. This pharmacodynamics profile then provides for a prolongation of inhibition of gastric acid output and correlates well with its more beneficial therapeutic efficacy over omeprazole and some of the other proton-pump inhibitors.
Esomeprazole will be well proven as an effective agent in the treatment of gastro-esophagitis reflux disease as it has a good tolerability profile and a low potential for drug interaction. (8) Esomeprazole has proven to provide better acid control and more favourable pharmacokinetic compare to currently used racemic PPIs. The treatment with a single oral dose of esomeprazole resulted in a greater total area under the plasma concentration-time curve and a more rapid increase in gastric pH than the same dose of other racemic omeprazole. An 8-weeks clinical trial was done involving the patient with erosive esophagitis in which treatment group receiving esomeprazole showed significantly higher healing rate then patient receiving lansoprazole and omeprazole. (9)
Esomeprazole is available in delayed release capsule as opaque, hard gelatin, amethyst coloured capsules in two strengths 20mg and 40mg. The delayed-release oral suspension is available in 2.5 mg, 5 mg, 10 mg, 20 mg or 40 mg – unit dose packet containing a fine yellow powder, consisting of white to pale brownish esomeprazole granules and pale yellow inactive granules (5). Each packet of esomeprazole for delayed-release oral Suspension contains either 20 mg or 40 mg of esomeprazole, the same active ingredient used in esomeprazole capsules. The esomeprazole granules and inactive granules used in this formulation are mixed with water to form a suspension and are given by a oral, nasogastric or gastric administration. Esomeprazole is also available as enteric coated tablets and intravenous injection/infusion. For some patient, injection is associated with pain and discomfort. The intravenous route of administration has better absorption than other routes.
Delayed-release capsules should be swallowed whole but alternatively, for patients who have difficulty swallowing capsules, they can be opened, and the granules inside the capsule can be carefully emptied on to a food. For patients who have a nasogastric tube in place, esomeprazole delayed-release capsules can be opened and the intact granules can be emptied into a 60mL catheter tipped syringe and mixed with 50 mL of water. It is important that only the catheter tipped syringe is used when administering esomeprazole through a nasogastric tube. (5)
A multi-centre open-label study was done to assess the effectiveness of esomeprazole 40mg in GERD symptoms persisting in the patients receiving a full dose of other PPI. The patient who had received a daily full dose of PPI for week 8, but still persisting suffered from GERD symptoms, were treated with esomeprazole 40mg for 8 weeks (n=99). The primary outcome of this study was the change in the frequency of heartburn. The patients’ outcomes were assessed using the GERD Impact Scale (GIS) and the Reflux Disease Questionnaire (RDQ). The result showed that the frequency of heartburn was reduced by 78% from 4.4 days a week to 1 day a week at the end of the 8 week treatment period. (p