• describe the symptoms of a peptic ulcer;
• explain how the secretion and motility of the stomach is controlled;
• outline the mechanism of gastric acid secretion and the mode of action of H2 antagonists and proton pump inhibitors;
• outline the lifestyle advice which is appropriate for peptic ulcer patients.
Part 1
Patterson, a young TV producer, leads a high-pressure life, smoking more or less continuously, eating irregularly and drinking large amounts of strong coffee to keep him going. His alcohol consumption is also high as he often feels the need to ‘chill out’ with a bottle of wine in the evening. He has little time to cook and many of his evening meals are takeaways.
Patterson has suffered from peptic ulcers for several years. His symptoms include acute bouts of central chest pain just below the sternum (epigastric) with nausea and sometimes vomiting. In between these episodes, he suffers from heartburn. His symptoms sometimes wake him at night and are worse when he has eaten late, just before retiring to bed. He takes antacids to control mild symptoms and, when the condition becomes severe, takes a prescribed H2 antagonist, ranitidine.
As a New Year resolution, Patterson decided to reduce his smoking, alcohol and coffee consumption, realizing that they made his symptoms worse. However, in spite of this, his pain has recently become more frequent and severe. On some nights, Patterson can only sleep if propped up by several pillows.
What are the functions of the stomach?
The stomach acts as a temporary reservoir for food and as a mixing chamber, allowing small amounts of gastric contents (chyme) to enter the duodenum at intervals. The acid environment and mechanical activity in the stomach starts the breakdown of food items and the acidity of the stomach eliminates many infectious organisms present in ingested material. Finally, an important function is the production and secretion of intrinsic factor, a compound that is necessary for effective absorption of vitamin B12 from the diet.
Where do peptic ulcers commonly occur in the gastrointestinal tract?
Peptic ulcers can occur in the duodenum and anywhere in the stomach, although they are usually located along the lesser curvature and in the pyloric region. Duodenal ulcers make up approximately 80% of the peptic ulcers diagnosed and occur in the first part of the duodenum.
Which cells in the stomach secrete HC1 and pepsinogen?
The cells which produce HC1 are the parietal cells; acid secretion can produce a stomach pH of 1.5-2. H+ is secreted into the stomach lumen by an ATP-dependent proton pump in exchange for K+. H+ secretion depends on the dissociation of carbonic acid, formed by the hydrolysis of CO2, in a reaction catalysed by carbonic anhydrase:
C02 + H20 ß carbonic anhydrase à H2CO3 ß à HCO3– +H+
As the H+ is pumped into the lumen of the stomach, HCO3– moves out of parietal cells into blood and Cl– enters the cell in exchange. Acid secretion is stimulated by histamine acting on H2 receptors, by acetylcholine acting on muscarinic (Ml) receptors and by gastrin acting on gastrin receptors of the parietal cells.
Pepsinogen is secreted by chief cells in the gastric mucosa and is the precursor of the protease enzyme pepsin.
In addition to HCl, the parietal cells produce intrinsic factor, which binds to dietary B12 and facilitates its absorption in the ileum. Gastrin, a hormone which promotes secretory activity in the stomach, is also produced by the gastric mucosal cells and released into the blood.
List the components of gastric secretion and the approximate volume of gastric juice secreted per day.
Water, mucus, pepsinogen and gastric lipase, which digests milk fats, are produced by the stomach. In young animals, rennin is also present in gastric secretions. The volume of secretion produced each day is approximately 21.
How is gastric secretion controlled before food enters the stomach and during a meal?
Gastric secretion is controlled in three phases:
(1) The cephalic phase, which is initiated by the sight, smell or thought of food before it enters the mouth. This is a nervous mechanism, mediated by the vagus.
(2) The gastric phase, which occurs when food actually enters the stomach. The presence of food and the composition of gastric contents stimulate local reflexes involving intrinsic nerve plexuses and stretch receptors and initiate release of gastrin from G cells to further enhance secretion.
(3) The intestinal phase, which occurs as chyme enters the duodenum. This involves many inhibitory controls: neural and endocrine mechanisms limit the rate of stomach emptying so that the secretory and absorptive mechanisms of the small intestine can cope effectively with the entry of gastric contents.
Describe the normal motility of the stomach and the factors which promote gastric emptying.
The stomach generates regular peristaltic waves which spread over the body of the stomach to the antrum and close the pyloric sphincter. Increased gastric motility occurs during a meal because of distension by the food, the activity of the vagus nerve and gastrin. When fat or excessive acid is present in the stomach, gastric emptying is slowed. Emptying chyme into the duodenum stimulates stretch receptors and initiates the enterogastric reflex, which temporarily inhibits gastrin secretion and gastric motility.
The presence of chyme in the duodenum also causes release of secretin, CCK and gastric inhibitory peptide (GIP), which also reduce gastric activity. The main function of secretin and CCK is to stimulate release of fluid and enzymes from the pancreas to ensure that suitable pH and enzymic activity is available for digestion. The rate at which chyme enters the duodenum is increased if a meal is large, distends the stomach greatly and contains alcohol and/or wine. All these factors stimulate gastric secretion and motility.
What is heartburn and how might use of extra pillows help Patterson to sleep?
Q7 Heartburn is a condition associated with reflux of gastric acid into the oesophagus. Normally, the contraction of circular muscle in the wall of the oesophagus acts like a lower oesophageal sphincter to prevent backflow (reflux) of acid material upwards from the stomach. When the stomach is full, lying down after a meal may allow acid to slip back along the oesophagus causing some patients to suffer burning pain in the chest (heartburn). When a person is upright, gravity helps to reduce the effects of acid reflux.
The problem of acid reflux is particularly marked in patients with a hiatus hernia, a condition in which part of the stomach protrudes into the thoracic cavity. Such patients find that heartburn is made worse by bending or lying down. Sleeping propped up by pillows makes the upper body more vertical and allows gravity to assist in minimizing the effects of gastric reflux in affected individuals.
Part 2
Patterson is referred to a gastroenterologist for endoscopy to examine the gastric mucosa. There are signs of inflammation in both the antrum and body of the stomach and an area of ulceration is visualized in the pylorus. Tests for Helicohacter pylori (H. pylori) are positive. Patterson was treated successfully with a course of antibiotics to eradicate the H. pylori infection and a proton pump inhibitor.
What is a peptic ulcer?
A peptic ulcer is an area of erosion on the gastrointestinal mucosa. Ulcers commonly occur in the duodenum and stomach, causing discomfort and pain. Development of ulcers appears to be the result of an imbalance between the mucosal defence mechanisms, which include mucus production, and agents, such as acid and pepsin, which can erode the mucosa. If the quantity of acid increases or the efficiency of the defence mechanism diminishes, ulcers form.
How does the normal stomach protect itself against digestion by the mixture of HCl and pepsin in gastric juice? How do over-the-counter medicines such as ibuprofen and aspirin and infection with H. pylori affect this mechanism?
The stomach secretes a very acid gastric juice with a pH of 1.5-2. The mucosa is normally protected from acid by a number of mechanisms. Mucus is produced by the large number of mucous cells in the body and fundus. It contains glycoproteins called mucins, and the mucus produced forms a kind of gel which coats the mucosal surface. In addition these cells secrete HCO3–, which is trapped in the mucus and increases the local pH to form a less acidic environment at the surface of the epithelial cells.
Prostaglandins (PGs) produced by the gastric mucosa stimulate the secretion of bicarbonate and mucus and inhibit the proton pump. Agents which block the synthesis of PGs, for example non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen, reduce the production of the protective PGs and predispose patients to the development of ulcers.
In recent years it has become clear that Helicohacter pylori infection is also important in the development of ulcers. The infection apparently upsets the balance between the protective mechanisms and the eroding effects of acid and pepsin: antibiotics are generally given to eradicate the infection and this is an effective treatment for achieving long-term healing of peptic ulcers.
Are any pharmacological agents available which can increase protection of the gastric mucosa?
Misoprostol is a synthetic PG analogue which is used to promote ulcer healing in patients who have ulceration related to use of NSAIDs, for example for chronic musculoskeletal pain. Its use can prevent the development of peptic ulcers as it has a protective effect on the mucosa.
Why may reduction in alcohol and caffeine help relieve Patterson’s symptoms?
Both alcohol and the caffeine content of coffee act directly on the gastric mucosa to stimulate acid and pepsinogen secretion, so reduction in their use should help the patient. Smoking can also worsen dyspepsia (indigestion) and heartburn, possibly via actions of nicotine on the stomach wall.
What is the overall aim of the pharmacological treatment of peptic ulcers?
Pharmacological treatment of peptic ulcers aims to restore the balance between mucosal defence and mucosal damage by acid and pepsin in the stomach wall. The general mechanisms of drug action include: (i) inhibition of acid secretion, (ii) neutralization of the acid with antacid preparations, (iii) eradication of Helicohacter pylori with antibiotics and (iv) enhancement of the mechanisms which protect the mucosa.
What is the mechanism of action of ranitidine?
Ranitidine is an example of an antagonist at histamine receptors on the parietal cells and has been in use for some years in the treatment of peptic ulceration. It blocks the H2 receptor on these acid-secreting cells, so reducing or preventing the activation of the H+-K+ ATPase proton pump and the production of HCl. It can heal both gastric and duodenal ulcers.
An alternative drug mechanism to reduce gastric secretion is proton pump inhibition. How do proton pump inhibitors reduce secretion?
Proton pump inhibitors, for example omeprazole, greatly reduce secretion of gastric acid by a direct inhibitory action on the proton pumps of the parietal cells, which secrete H+ into the stomach lumen. They are used alone or in combination with the eradication of H. pylori, generally for treatment of severe reflux disease.
What general advice would be suitable to give to people, like Patterson, who suffer from recurrent ulcer problems?
In addition to eradication of his Helicohacter pylori infection and a short course of a proton pump inhibitor, Patterson would benefit from regular small meals which include fruit and vegetables instead of one large meal at night. Preferably, he should have his last meal of the day several hours before retiring to bed. Reducing his consumption of alcohol and coffee, which stimulate acid secretion, and high-fat meals, which prolong the secretion of acid, will also help. Weight reduction, smoking cessation and, perhaps, raising the head of his bed a little should also help reduce his gastric reflux.
Key Points
• The stomach stores and mixes food with gastric acid secretions: stomach pH is 1.5-2. Gastric acid can erode areas of the stomach and duodenal mucosa to cause peptic ulcers if the alkaline mucus, which normally protects the mucosa, is reduced or lacking. Symptoms produced include: pain, nausea and vomiting. Alcohol, caffeine from coffee and smoking stimulate acid and pepsinogen secretion, making symptoms of peptic ulcer worse.
• Infection with the bacterium H. pylori is associated with ulcer development. Treatment of peptic ulcers may involve a course of antibiotics to eradicate this organism. Agents such as H2 (histamine) antagonists, for example ranitidine, and proton pump inhibitors, such as omeprazole, are also used to heal peptic ulcers.
• PGs produced in the gastric mucosa stimulate the secretion of both bicarbonate and the mucus gel to protect the mucosa from damage by gastric secretions. Use of NSAIDs, such as aspirin and ibuprofen, reduces the production of the prostanoids and so decreases the protection of the gastric mucosa, promoting mucosal erosion.
• Gastric secretion and motility are controlled by both nervous and hormonal mechanisms. The vagus initiates the cephalic phase of secretion in response to the sight or smell of food, before food is eaten. The gastric phase occurs when food enters the stomach and is controlled both by intrinsic nerve reflexes in the stomach wall and released gastrin. The third, or intestinal, phase of secretion is coordinated by nervous and hormonal mechanisms to limit the release of the chyme from the stomach into the duodenum and reduces further acid secretion.
• Heartburn, a burning pain in the chest, is due to reflux of gastric acid from the stomach into the oesophagus. This worsens when patients lie down or bend down after eating a meal. If a person is in an upright position, gravity helps to reduce acid reflux. Heartburn is treated with proton pump inhibitors and H2 antagonists. Patients are advised to reduce smoking, alcohol and coffee intake, to eat the last meal of the day some hours before retiring to bed and take regular, small, low-fat meals, rather than one large meal in the evening.
Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.