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Peptic ulcer refers to an ulcer which can be seen in lower esophagus, stomach or duodenum, in the jejunum after surgical anastomosis to stomach or, rarely, in the ileum adjacent to a Meckel's diverticulum as an ulcer (1).A peptic ulcer of the duodenum is called a duodenal ulcer, of the stomach, a gastric ulcer and of the esophagus, an esophageal ulcer (2). Duodenal ulcers and gastric ulcers may be acute or chronic (1). Duodenal ulcers are more common than gastric ulcers. 10 - 15% of the population will suffer from duodenal ulcer (3).
Occurrence of peptic ulcer disease is decreased in many western communications. Because of wide spread using of H. pylori eradication therapy. But it is highly spread in developing countries (1). The medical cost of treating peptic ulcer is very high and it will be the reason for this situation (2).
Clinical features and symptoms
The main characteristic feature is pain from the epigastrium and it is very useful feature to the doctor to diagnose the disease. Pain related to the meal is not a significant feature as it varies from one patient to another patient and one ulcer type to another ulcer type. Anorexia and weight loss also may be the features of peptic ulcer and nausea also associated with the pain. Vomiting is not so referred to the pain. But sometimes in severe peptic ulcers it may be asymptomatic. If someone has severe and continuous pain the ulcer may have spread to other visceral organs. As well as severe back pain is a feature which can be identified the penetrating posterior ulcer. If the patient doesn't take treatments for the ulcers it may worsen (3).
How to diagnose
Under non invasive method 13C Urea breath test, serological test and stool test are done for diagnosis of peptic ulcer infected with H.pylori. 13C Urea breath test is quick and easy way among other tests. Measuring 13CO2 in breath after ingestion13C Urea by using spectrometer is the method of this test. Serological test detect IgG antibodies and the test is used to epidemiological studies. Monoclonal antibodies are used for the stool test. In invasive (endoscopy) method rapid urease test is done by adding gastric biopsy into urea, phenol red mixture (3).
Complications of peptic ulcer
Hemorrhage is one of complication of peptic ulcer. Bleeding is caused by the ulcers. Perforation is another complication which can attributable partly to medical therapy. Duodenal ulcers are more perforated than gastric ulcers to peritoneal cavity (3).
Peptic Ulcer Illustration - Peptic Ulcer Disease(2)
Causes for peptic ulcers
In the past as we believed that the excess acid secretion is the major cause of ulcer disease the treatments were depended on neutralizing and inhibiting the secretion of stomach acid. But there are two most important initiating causes of ulcers. Infection of the stomach by a bacterium called "Helicobacter pyloricus" (H. pylori) who is a spiral shaped Gram- negative urease producing bacteria and continual use of anti-inflammatory medications, commonly referred to as (nonsteroidal anti-inflammatory drugs) NSAIDs, includingÂ aspirin. As well as cigarette smoking is an important cause for ulceration (2, 3, 6, 8, 13).
Half of United States population older than age 60 is infected withÂ H. pylori and Infection leads to ulcer disease about 15% of those infected. On the other hand 80% of patients with gastric and duodenal ulcers are infected with H. pylori. Increasing appreciation, diagnosis and treatment of this infection, cause to decrease the wide spread of infection withÂ H. pyloriÂ and the proportion of ulcers with H. pylori infections. How ever now only 20% ulcers are H. pylori infected. By using antibiotics it is able to heal ulcers and prevent the recurrence of ulcers (2).
In some conditions H. pyloriÂ are in the stomachs of people without causing to make any pain or ulcer. So it is difficult to take a decision whether treating that patient with antibiotics or not. As eradication of H. pylori is not easy it should be done by using antibiotics with a proton-pump inhibitor, Pepto-Bismol or H2 blockers (3, 8).
For arthritis and other painful inflammatory conditions NSADI which is non steroidal anti inflammatory drug is used as a treatment. Aspirin, ibuprofenÂ (Motrin),Â naproxen (Naprosyn), andÂ etodolacÂ (Lodine) are drugs which affect on peptic ulcers (2, 8, 13).
Stomach cancer is also a reason which affect to the peptic ulcers (6).
Cigarette smoking causes ulcers. As well as it causes to complications from the ulcers like bleeding, stomach obstruction, and perforation. It helps for the unhealing ulcers and ulcer recurrence.
Coffee, alcohol, spicy foods, colas, andÂ caffeine can't affect on ulceration more effectively. Life stresses also not a more relevant cause for ulcer formation (2, 8, 9).
Some drugs have been found and available in united state as therapy to patients with peptic ulcers including the H2 receptor an agonists and sucralfate. Although antimuscarinic agents, omeprazole, misoproto and antacids are marketed they are not recommended (4)
Acid out put (mmol/hr)
Treatments for patients with peptic ulcer mainly depend on antibiotics to kill the H. pylori bacterium and other medications to reduce the acid level in digestive system(5) In most of these procedures , if acid secretion is reduced ,it involve with this system. First, the vagus stimulation is decreased. Impulses of vagus lead to secrete acid. So decreased vagal stimulation cause to reduce gastric secretion gastric is a acidic juice which helps to unheal the ulcers. As well as pepsin is a protein digesting hormone. So that it may cause to damage membranes also. So preventing this gastric secretion is useful to heel ulcers. (4)
In treatments for peptic ulcer
Antibiotics to kill H. pylori
Reducing acid production
Blocking acid secretion and promote healing.
Antacids that neutralize stomach acid.
Protecting the lining of the patients stomach and small intestine
are included (1, 2, 3).
Antibiotics to kill H. pylori
When H. pylori are found in the patient in digestive system, combination of antibiotics to kill the bacterium should be recommended. For the treatments of H. pylori amoxicillin, clarithromycin (Biaxin), metronidazole (Flagyl) tetracycline and levoarfloxacin (levaquin) are given to the patients with peptic ulcer. Antibiotics are used for two weeks (2). Treatment is based on proton pump inhibitor and the treatment is successful 90% of treated patients although side effects, complications and metronidazole resistance control the success of the therapy (1). Treating to children who are infected with H pylori is done in combination with pylori amoxicillin, clarithromycin (Biaxin), metronidazole (Flagil) and tetracycline. This helps to stop recurrent ulceration. Not only that, it cause to prevent developing gastric cancers. But this treatment causes to make diarrhea, allergic reactions, and inflammation in the colon (2).
The H.pylory eradication therapy is a one week course using drugs twice a day with two antibiotics ofmetronidazole 400mg and clarithromycin 250mg, or amoxicillin 1g and clarithromycin 500mg and a full-dose proton pump inhibitor. Some patients have to get the secondary treatments and it consists of proton pump inhibitor, bismuth subcitrate, amoxicillin, metronidazole for 2 weeks (6).
Reducing acid production
Histamine (H-2) blockers are the acid blockers which can reduce the releasing of acid into the digestive tract. Acid blockers like ranitidine (Zantac), famotidine (Pepcid), cimetidine (Tagamet) and nizatidine (Axid) are used for treatments. As well they help to relief pain of ulcers. (2)
Blocking acid secretion and promote healing
Blocking the action of acid secreting parietal cells is the way of stop acid secretion by proton pump inhibitors. The proton-pump located at the luminal side of the mucous membrane is responsible for HCl secretion and can be blocked with below drugs. Using this proton pump inhibitors for a long time will affect on hip, wrist and spine fracture. The risk will be reduced by supplementation of calcium. Omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), esomeprazole (Nexium) and pantoprazole (Protonix) are used as drugs (2, 9).
Antacids that neutralize stomach acid
Antacid can neutralize the stomach acid and can relief the pain. Constipation or diarrhea may occur as a result of using these drugs (2).
Protecting the lining of the patients stomach and small intestine
Mucosa, sub mucosa and muscles which are in stomach and intestine are protected by tissues. Cytoprotective agents protect the tissues that line stomach and small intestine. Sucralfate (Carafate) and misoprostol (Cytotec) are prescribed drugs (2).
Although peptic ulcer can be cured by medical therapy, some patients with complications like hemorrhage, perforation or obstruction requires this therapy (4, 6). When the patient can't be cured by medications endoscopy should be done before the surgery to make sure that the pain occur as the ulceration and there is no any other cause for the pain (4). Vagotomies are more physiologic in nature and produce less postoperative symptoms. So it is valuable feature for treating patients (12). There are main three types of surgeries according to the way of doing it.
Cutting nerves (vagus nerves which supply the parasympathetic stimulation) of stomach is one way and it is called vagotomy. Second way is removing a part of stomach which is called partial gastrectomy. Another way is doing these two surgeries in combinations (6, 7). We can define the surgeries by considering other conditions.
Subcostal gastrectomy is done to duodenal ulcer disease and rarely use to gastric ulcers. 90- 95 % of surgeries are successful and effectiveness for prevention of ulcer recurrence. But it causes to make more post operative complications (4).
Truncal vagotomy and pyloroplasty
Vagotomy reduces basal acid secretion by 80 - 90% and eliminates vagal stimulation which cause to acid secretion. Truncal vagotomy leads to delay gastric empting. Vagotomy and pyloroplasty are used to treat patients with bleeding ulcers and with intractable ulcer disease.4
Truncal vagotomy and antrectomy.
In this surgical procedure, mucosa which contains the gastrin is removed and gastric phase of food - stimulated acid secretion is diminished. If we do only antrectomy it causes to reduce acid secretion. Antrectomy with a vagotomy cause to reduce greater reduction of acid out put. Antrectomy with truncal vagotomy is used frequently for duodenal ulcer disease, because ulcers come back rarely after this surgical procedure. But long term post operative complications occur frequently (4).
Proximal gastric vagotomy
Proximal gastric vagotomy can reduce acid secretion while maintaining normal gastric empting. Reducing acid secretion with minimal mortality and long term postoperative morbidity is the advantage of this procedure. This commonly used for duodenal ulcers (4). As chronic ulcers cause to scaring of pylorus and duodenum which can be a reason for delaying gastric empting, it is treated with a surgical therapy creating a short cut to empty y the gastric juice.
Late postoperative complications
Postprandial dumping occurs when pyloric mechanism is disrupted by pyloroplasty, gasrroduodenostomy or gastrojejunostomy.
Post vagotomy diarrhea
In vagotomy, Post vagotomy diarrhea is a common feature.
This feature also can signify from the patient who has got a surgical therapy.
After antrectomy Weight loss occur as a result of inadequate caloric intake.
Deficiency of iron, vitamin B12 or folate causes to the anemia after the surgery for ulcers.
Alkaline reflux gastritis and esophagitis
A gastritis and esophagitis is caused by refluxing of duodenal contents, bile in to the remains of gastric.
Afferent loop syndrome
Afferent loop syndrome occurs in patients after gastroenterostomy as a result of pancreatic and biliary secretions collect in a partially obstructed afferent loop causing pain (4, 6).
Mechanism of gastric acid secretion
The parietal cell secretion is probably an isotonic solution of HCl that contains 150 meq of chloride and 150 meq of hydrogen ions per liter as the purest specimens of parietal cell secretion that have been obtained contain normally 0.17 N HCl, with pHs as low as 0.87. The pH of cytoplasm is similar to other cells (7.0-7.2) and the comparable concentrations per liter of plasma are about 100 meq of chloride and 0.00004 meq of hydrogen ions.
It is H+/K+ ATPase in the apical membrane of parietal cells that pumps hydrogen ions against a concentration gradient of the magnitude. The parietal cells are polarized with an apical membrane facing the lumen of gastric glands and a basolateral membrane in contact with the interstitial fluid. Canaliculi extend from apical surface into the cell. At rest, the cells contain abundant tubulovesicular structures with H+-K+ ATPase molecules in their walls. Tubulovesicular structures move to apical membrane and fuse with it when the parietal cells are stimulated, thus inserting many more H+-K+ ATPase molecules into the membrane. Now those molecules are exposed to K+ in extra cellular fluid and H+-K+ exchange begins.
Cl- is also extruded down its electrochemical gradient through the channels that are activated by cAMP. Hydrogen ions that are extruded come from H2CO3, and H2CO3 in turns is formed by hydration of CO2. The HCO3- formed by dissociation of H2CO3 is extruded by an antiport in the basolateral membrane of parietal cells that exchanges HCO3- for another anion and because Cl- is the most abundant anion in interstitial fluid, the exchange is mainly for Cl- (10)
REGULATION OF GASTRIC ACID SECRETION
There are three stimulants of gastric acid secretion named acetylcholine, gastrin and histamine which can act physiological roles in regulation of secretion. There are receptors controlling oxyntic cell secretion for histamine, acetylcholine, gastrin and prostaglandins.
Acetylcholine acts directly on parietal cells and it is released by vagal and intramucosal reflex stimulation. Gastrin is the only known hormonal stimulant of acid secretion. It is released by peptides and free amino acids in the stomach. Acetylcholine can release gastrin. Cholinergic control of gastrin release is very complex because anticholinergic drugs may increase gastrin release under certain conditions although histamine regulating factors haven't been defined yet, there is a belief that histamine has an important role in acid secretion. This doubt was left with H2-receptor antagonists.
Studies with isolated parietal cells indicate that histamine, acetylcholine and gastrin each act at different receptors on parietal cell. Anticholinergic agents specifically prevent cellular actions of acetylcholine, cimetidine specifically inhibits stimulation by histamine and neither inhibitor blocks the small direct response to gastrin.
And also potentiating interactions occur between histamine, gastrin and cholinergic agents which may account for the interdependence of secretagogue action observed in vivo. Although direct potentiating interactions occur between gastrin and histamine carbachol, direct potentiating interactions don't occur between carbachol and gastrin. But in presence of histamine, gastrin and carbachol a three-way potentiation occurs. By interfering with the potentiating interactions between anticholinergic agents cimetidine and stimulants display an apparent cross-specificity in vitro which resembles the effects of those agents in intact mucosa. Mechanisms underlying those interactions are not identified, but actions of histamine may be mediated through increased production of cyclic adenosine mono phosphate (AMP) and AMP analogs which mimic the interactions involving histamine itself. Secondary effectors for gastrin and acetylcholine and mechanisms for amplification of response to combinations of stimulants remain to be elucidated (9, 10).
Drugs used to treat peptic ulcer disease
Antacids and alginates
Alginates form protective mucosal 'raft'. Aluminium hydroxide, magnesium trisilicate, alginic acid are examples for antacids and alginates. Aluminium salts block digoxin absorption and they are constipating. As well as magnesium salts cause diarrhea. Some of them have high sodium content and it will intensify cardiac failure (1).
H2 - antagonist
They act as competitive inhibitors of H2 - receptors on parietal cells and ECL cells. Ranitidine, cimetidine, famotidine, nizatidine are some of examples for H2 - antagonist (1, 7). These drugs are less potent than proton pump inhibitors. But they are good safety profile and after treating to stomach ulcers with H2 - antagonist that patients should be examined with gastroscopy (1, 6). Cimetidine will interfere with warfarin and phenytoin metabolism via cytochrome P450 (1).
Proton pump inhibitors
Omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole are examples for Proton pump inhibitors. These are irreversible inhibitors of H+/K+ ATPase on parietal cell surface. These drugs cause to potent acid suppression and rapid ulcer healing. As well this is used in H. pylori therapy and superior to H2 - antagonist to healing ulcers and esophagitis (1).
. Action of this drug helps to anti H. pylori activity and it enhances the mucosal protection. In pediatrics antibiotics and bismuth sulfate is used in combination with proton pump inhibitors to treat H. pylori infection (11).how ever this cause to make darken tongue and stools. Tripotassium dicitratobismuthate is an example for Chelates (1).
Sucralfate is an example for Complex salts. Aluminium salt of sucrose octasulphate effects on acid and it will protect ulcer base from peptic activity and enhance epithelial cell turnover. As a result of using this drug renal impairment and bezoar formation may occur.
Enhancing mucus blood flow, stimulating mucus and bicarbonate secretion, stimulating epithelial proliferation are the actions of this drug (1). Prostaglandins can help to the linings of the esophagus, stomach, and duodenum to resist damage by the juices of stomach which are acidic. NSAIDs act against the prostaglandins in the stomach and it cause to delay ulcer healing (2). Misoprostol is an example for prostaglandin analogues. Diarrhea and abortifacient are expected as bad effects of using prostaglandin analogues. For the women in child - bearing age this is not a suitable drug as it is contradicated for them (1).
Complementary factors in peptic ulcer therapy.
Diet, smoking alcohol or analgesic use, sedatives and the need for hospitalization are the factors to be considered.
This is a one of slandered treatment of peptic ulcer disease. If some food cause to make the patient discomfort , he should avoid that food. As well as the patient can eat whatever he likes. Specially milk stimulates acid secretion between meal or bedtime.
Non smoker's ulcer healing is more often and more rapidly than smokers. Not only that, non smokers have so many benefits like preventing from carcinoma than healing ulcers. Components of cigarettes reduce endogenous generation of prostaglandins. But the mechanism of effecting on peptic ulcers is unknown.
Although alcohol damage gastric mucosa, it can't retards ulcer healing.
Aspirin, non steroidal anti - inflammatory drugs [NSAID] inhibits the synthesis of prostaglandin and they are ulcerogenic.as well as they can produce gastric lesion (3). But predispose an ulcer to bleed. Patients with documented ulcer disease shouldn't continue the agent at all possible. Although patients with non healing ulcers shouldn't get NSAID or aspirin, patients, who have to use NSAID continuously, should get prophylactic therapy with misoprostol gastric ulcer or H2 receptor antagonist with documented ulcer.
In some patients, emotional stress cause to pathogenesis of peptic ulcer. In ulcer therapy routine use of these drugs isn't cause to benefits.
Patients with complications like bleeding, perforation, penetration, obstruction or patients with pain full ulcer , should be hospitalized.
Initial management of peptic ulcer
Full -dose regimen of an H2 receptor antagonist or sucralfate for and H2 receptor antagonist to peptic ulcer. Duodenal ulcer patients should be treated 4-6 weeks and if the patient is cured the therapy is stopped without doing further treatments. But gastric ulcer patient is treated for 8 weeks, after doing the endoscopy or barium radiography. If it is not show any wrong treatments are stopped.
Management of patients with unhealed ulcers
If some ulcer is unhealed after the initial therapy, they should stop smoking and aspirin or NSAID usage. Some times duodenal ulcer can be treated by the dose of H2 receptor antagonist or change to omeprazole, development of compliance like bleeding while doing medical therapy or non compliance will command surgery. In unhealed gastric ulcers dose of H2 receptor antagonist should be increased or therapy changed to omeprazole. If it is unhealed further it should be considered that whether it is a cancer, by doing a biopsy. (4)
Long term maintenance therapy
It is done with H2 receptor antagonist or sucralfate. This therapy causes to reduce the recurrent ulcer. It is not necessary for all patients with peptic ulcers. Patients who have bled with ulceration have to get maintenance therapy to stop the re-bleeding.
Treatments of patients with Zollinger-Ellison syndrome are also important to reduce peptic ulcers. Patients with Zollinger-Ellison syndrome are in a risk of ulceration as it causes to increase the secretion of acid. These patients' clinical presentations are to peptic ulcer disease with the additional feature of diarrhea (11). In earlier, total gastrectomy was the treatment for these patients. All the acid secretion mucosa is removed in vagotomy. H2 receptor antagonist and omeprazole was an effective way of treating patients with peptic ulcer. For reducing acid secretion with H2 antagonist or omeprazole, it requires frequently administration (ex: - "600mg of cimetidine every4 hours or 300mg of aranitidine every 8 hours"may be necessary to reduce acid secretion adequately.) some of them want even large and more frequently doses of H2 receptor antagonist ("few patients requires 5-10 g cimetidine daily ") treating patients along with an antimuscarnic drug such as glycopyrrolate or isopropadine cause to reduce the dose of H2 receptor antagonist.
As complications occur in patients and medical therapy can't give an opportunity to search resectable tumors, medical therapy can't be applied alone with H2 antagonist or omeprazole (4).