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Review Article New Pharmacological Therapies for Treatment of Gastroesophageal Reflux Disease

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Review Article New Pharmacological Therapies for Treatment of Gastroesophageal Reflux Disease Journal of Pharmaceutical Research & Clinical Practice, Oct-Dec 2013; 3(4):11-21 Review Article New Pharmacological Therapies for Treatment of Gastroesophageal Reflux Disease *Rahul Saini1, Shanmukhananda M. P.2, Sunaina3 1. Department of Pharmacology, PGIMS, Rohtak, India. 2. Novartis, Hyderabad, India. 3. Department of Radiology, PGIMS, Rohtak, India. ABSTRACT Gastroesophageal reflux disease (GERD) is a chronic, relapsing disorder characterized by recurrent symptoms of acid reflux with esophageal injury. It rarely resolves spontaneously, and it is associated with frequent recurrences. It has adverse impact on quality of life. A variety of medications have been used in GERD treatment, and acid suppression therapy is the mainstay of treatment for GERD. Although proton pump inhibitor is the most potent acid suppressant and provides good efficacy in esophagitis healing and symptom relief, about one-third of patients with GERD still have persistent symptoms with poor response to standard dose proton pump inhibitors (PPI). These are generally well tolerated but there are associated with minor side effects such as headache, diarrhea, and abdominal pain. Newer formulations of PPI which have faster and longer duration of action and potassium-competitive acid blocker, a newer acid suppressant, are also in developing stages. Transient lower oesophageal sphincter relaxation (TLESR) is an important factor behind the occurrence of reflux, and preclinical studies have identified gamma aminobutyric acid (GABA) type B receptor (GABAB) agonists and metabotropic glutamate receptor 5 (mG1uR5) modulators as candidate drugs for modifying TLESR. Another novel therapeutic agent has focused on the underlying mechanisms of GERD, such as motility disorder, mucosal protection, and esophageal hypersensitivity are also under clinical trials. Keywords: GERD, PPI, gastric acid, esophagitis Received 12 Sept 2013 Received in revised form 09 Oct 2013 Accepted 13 Oct 2013 *Author for Correspondence: Dr. Rahul Saini Senior Resident, Department of Pharmacology, PGIMS, Rohtak, India, E-mail: [email protected] INTRODUCTION Gastroesophageal reflux disease (GERD) is increased two- to six fold in the last 20 defined as “a condition which develops years [3]. when the reflux of gastric contents into the The normal antireflux mechanisms consist esophagus causes troublesome symptoms of the lower esophageal sphincter (LES), the (i.e., at least two heartburn episodes/week) crural diaphragm, and the anatomical and/or complications”[1].GERD is the most location of the gastroesophageal junction common digestive disease in the Western below the diaphragmatic hiatus. Reflux world, with an estimated prevalence of 10 – occurs only when the gradient of pressure 20% [2].With respect to the esophagus, the between the LES and the stomach is lost. It spectrum of injury includes esophagitis, can be caused by a sustained or transient stricture, Barrett's esophagus, and decrease in LES tone. A sustained adenocarcinoma. There were about 8,000 hypotension of the LES may be due to incident cases of esophageal muscle weakness that is often without adenocarcinoma in the United States in apparent cause. Secondary causes of 2010 (half of all esophageal cancers); it is sustained LES incompetence include estimated that this disease burden has scleroderma-like diseases, myopathy Rahul Saini et.al, JPRCP 2013; 3(4) 11 Journal of Pharmaceutical Research & Clinical Practice, Oct-Dec 2013; 3(4):11-21 associated with chronic intestinal pseudo- transverse the cell membrane, imparting obstruction, pregnancy, smoking, severe cellular injury in a weakly acidic anticholinergic drugs, smooth muscle environment, and has also been invoked as relaxants (β- adrenergic agents, a cofactor in the pathogenesis of Barrett's aminophylline, nitrates, calcium channel metaplasia and adenocarcinoma. Hence, the blockers, and phosphodiesterase causticity of gastric refluxate extends inhibitors), surgical damage to the LES, and beyond hydrochloric acid. esophagitis [3]. Reflux mainly occurs during Management prolonged relaxations of the lower The goals of treatment are to provide esophageal sphincter (LES) not related to symptom relief, heal erosive esophagitis, swallowing, now referred to as transient and prevent complications. Treatment lower esophageal sphincter relaxations approach is according to the level of (TLESRs) [4]. Such relaxations are a vago- severity (Table 1). The options include vagal reflex mediated motor pattern lifestyle modifications, medical and non- generated in the brain stem and triggered medical (Antireflux surgery) management. by distension of the stomach with free air or Lifestyle modifications include reducing ingestion of a meal [5]. Increased episodes weight, sleeping with the head of the bed of TLESRs are associated with GERD. Apart elevated by about 4–6 inches with blocks, from incompetent barriers, gastric contents and elimination of factors that increase are most likely to reflux when gastric abdominal pressure. Patients should not volume is increased (after meals, in pyloric smoke and should avoid consuming fatty obstruction, in gastric stasis, during acid foods, coffee, chocolate, alcohol, mint, hypersecretion states), when gastric orange juice, and certain medications (such contents are near the gastroesophageal as anticholinergic drugs, calcium channel junction (in recumbency, bending down, blockers, and other smooth-muscle hiatal hernia), and when gastric pressure is relaxants). They should also avoid ingesting increased (obesity, pregnancy, ascites, tight large quantities of fluids with meals. clothes). Incompetence of the Medical need for new drugs for GERD diaphragmatic crural muscle, which Due to high prevalence of GERD the medical surrounds the esophageal hiatus in the costs involved seems to be enormous. The diaphragm and functions as an external LES, prevalence of both typical and atypical also predisposes to GERD. Obesity is a risk GERD has significantly risen over the last factor for GERD. Acid refluxed into the decade, increasing the demand for adequate esophagus is neutralized by saliva. Thus, GERD treatment. Though proton pump impaired salivary secretion also increases inhibitors have been extremely effective for esophageal exposure time. If the refluxed both healing of erosive esophagitis as well material extends to the cervical esophagus as controlling heartburn symptoms for the and crosses the upper sphincter, it can enter majority of GERD patients, there is still a the pharynx, larynx, and trachea. Though substantial subclass of patients (up to 40%) the refluxed gastric juice is harmful to the who do not completely respond esophageal epithelium, gastric acid symptomatically to a standard dose of PPIs. hypersecretion is usually not a dominant Refractory gastro-esophageal reflux disease factor in the development of esophagitis. An (GERD), defined as persistent symptoms obvious exception is with Zollinger-Ellison despite proton pump inhibitor (PPI) syndrome, which is associated with severe therapy, is an increasingly prevalent esophagitis in about 50% of patients. condition and is becoming a major Pepsin, bile, and pancreatic enzymes within challenge for the clinician. The specific gastric secretions can also injure the explanation for PPI treatment failure is not esophageal epithelium, but their noxious clearly known. Possible pathophysiologic properties are either lessened in an acidic mechanisms include: transient lower environment or dependent on acidity for esophageal sphincter relaxations (TLESRs), activation. Bile is more dangerous because sensitivity to weakly acidic and/or alkaline it persists in refluxate despite acid- reflux, large volume of reflux, and suppressing medications. Bile can esophageal hypersensitivity [6]. Rahul Saini et.al, JPRCP 2013; 3(4) 12 Journal of Pharmaceutical Research & Clinical Practice, Oct-Dec 2013; 3(4):11-21 Table 1: Therapeutic approach in GERD patients according to the level of severity as follows [7]. Stage Criteria Medical management I Sporadic uncomplicated heartburn, often in setting Lifestyle modifications of known precipitating factor. Antacids and/or H2 receptor Often not the chief complaint. antagonists as needed Less than 2-3 episodes per week. No additional symptoms. II Frequent symptoms with or without esophagitis. Proton pump inhibitors more Greater than 2-3 episodes per week. effective than H2 receptor antagonists III Chronic unrelenting symptoms; immediate relapse Proton pump inhibitors either off therapy. once or twice daily Esophageal complications (eg: stricture, Barret’s metaplasia). Erosive esophagitis healing is one as partial or non-responders and require important trial endpoint, and a substantial further or alternative treatment, especially proportion of patients do not heal after in non-erosive reflux disease (NERD) standard doses of PPIs for 8 weeks. patients. Recent studies emphasize that Nonresponse of erosive esophagitis non-acidic reflux may also contribute to increases with severity of erosive symptom generation [12]. There may also be esophagitis grading. An intragastric pH of at a ceiling effect for the use of PPI therapy. least 4.0 maintained for 16 h is generally Thus there is a continuous need for new considered the target to promote healing of drugs for the better management of GERD erosive esophagitis with antisecretory patients. New inhibitors of the proton pump drugs [8]. Most patients will experience with a longer half-life, acting faster and reflux after midnight, when the supine
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