Gastro-oesophageal reflux disease and peptic ulcer disease By: Dr. Singanamala Suman Assistant Professor Department of Pharm.D
Gastro-oesophageal reflux disease and peptic ulcer disease Learning objectives: To understand acid secretion in the stomach To appreciate presentation of upper gastrointestinal disorders To recognise the role of Helicobacter pylori in gastrointestinal ulceration To identify properties of antacids and ulcer-healing drugs To develop skills to manage patients presenting with upper gastrointestinal disorders.
ACID SECRETION IN THE STOMACH In the parietal cells acid secretion is activated by stimulation of gastrin receptors, histamine type 2 receptors and muscarinic type 3 receptors. After stimulation, there is a common pathway through the H+/K+-dependent ATPase proton pump which releases H+ into the stomach lumen. Secretion is decreased by the stimulation of prostaglandin E2 (PGE2) receptors. Synthesis of the prostaglandin PGE2 is mediated via pathways involving cyclo- oxygenase type 1 (COX-1).
Gastro-oesophageal reflux disease Reflux into the oesophagus of the gastric or intestinal contents occurs which causes oesophagitis due to acidic contents coming into contact with the oesophagus. Patient complains of heartburn. Risk factors: pregnancy, obesity, foods with high fat content, spices, citrus fruit, coffee. Occurrence increases at night when patient is in supine position.
Extra-oesophageal complications of gastro-oesophageal reflux disease Laryngopharyngeal disorders Dental erosion Sinus problems Reflux-induced asthma. Medications that relax the LES Benzodiazepines, Theophylline, Narcotics containing codeine., Calium channel Blockers Nitroglycerine Anticholinergics, Potassium supplements, Iron supplements, NSAIDS, Fosamax, Erythromycin
Lifestyle measures Achieve ideal body weight. Decrease cigarette smoking. Avoid foods that irritate gastric mucosa (spicy foods, citrus, tomato extracts), lower oesophageal sphincter pressure (chocolate, alcohol, peppermint, fatty food) or stimulate secretion (cola, beer). Elevate head of bed.
Dyspepsia This is described as persistent or recurrent abdominal discomfort in the upper abdomen. Of patients presenting with dyspepsia: 50% have an underlying cause 20% have abnormalities 30% have no underlying cause or physical abnormality.
Management guidelines for dyspepsia Symptom evaluation and history: alarming symptoms or age >50 years: endoscopy no alarming symptoms, age <50 years symptoms <4 weeks: treat and monitor. Test for Helicobacter pylori: positive result: eradication therapy negative result: empirical therapy: H2-receptor antagonists, or proton pump inhibitors.
Peptic ulcer A lesion in the lining (mucosa) of the digestive tract, typically in the stomach or duodenum, caused by the digestive action of pepsin and stomach acid. This is the occurrence of discontinuity in the entire thickness of the gastric or duodenal mucosa that persists and results from acid and pepsin in the gastric juice.
Epidemiology Diseases associated with peptic ulcer include: chronic pulmonary disease cirrhosis of liver chronic renal failure pancreatic insufficiency. Potential risk factors are: cigarette smoking psychological stress genetic factors diet H. pylori infection.
Pathogenesis of PUD H. pylori infection: 95% of duodenal ulcers and 80 85% of gastric ulcers are due to the occurrence of this microorganism in the gastrointestinal tract. Use of NSAIDs may cause: superficial erosions and haemorrhages silent ulcers ulcers causing clinical symptoms and complications. NOTE: Enteric-coated preparations of NSAIDs prevent physical damage during drug dissolu- tion but do not reduce ulcer risk since damage is due to systemic action by reducing mucosal prostaglandin production.
Clinical manifestations Upper abdominal pain Anorexia Weight loss Nausea and vomiting Heartburn and eructation Haemorrhage, chronic iron deficiency anaemia, perforation.
Investigations Endoscopy: very sensitive and reliable test, invasive and some patients refuse to undergo this investigation Radiology: using double-contrast barium radiography H. pylori detection: using serological tests to detect antibodies.
Goals of therapy in uncomplicated peptic ulcer disease To provide relief from pain and other ulcer symptoms To promote healing To prevent complications of peptic ulcer disease To maintain adequate nutrition To prevent recurrence.
The European Helicobacter pylori Study Group (1997) recommendations When patients are diagnosed with H. pylori infection, the triple therapy eradication technique should be adopted. One week of triple therapy using a proton pump inhibitor,1 e.g. omeprazole 20 mg twice daily plus: amoxicillin 1 g twice daily and clarithromycin 500 mg twice daily amoxicillin 500 mg three times daily plus metronidazole 400 mg three times daily metronidazole 400 mg twice daily plus clarithromycin 250 mg twice daily.
Drugs used for prophylaxis of NSAID- induced ulceration In patients at risk of developing an ulcer such as elderly patients, patients who are taking drugs that may increase risk (e.g. SSRIs) or patients with a past history of gastrointestinal haemorrhage, prophylaxis may be considered using: misoprostol 200 micrograms twice to four times daily ranitidine 150 mg twice daily omeprazole 20 mg every day.
Drugs used in the treatment of PEPTIC ULCER Antacids: to counteract symptoms Drugs that inhibit acid secretion: H2-receptor antagonists proton pump inhibitors prostaglandin analogues Drugs that do not inhibit acid secretion, but have a cytoprotective effect: chelated bismuth salts sucralfate.
Antacids These products are weak alkalis that bring about neutralisation of the acidic ph in the stomach. They provide symptomatic relief in dyspepsia, peptic ulceration and gastro-oesophageal reflux. Antacids may be used when symptoms occur and provide relief generally within 5 15 minutes of administration. They should be administered between meals and at bedtime (relief duration ranges from 1 hour to 3 hours).
Systemic antacids sodium bicarbonate After oral administration it is absorbed and may cause alkalosis. It is usually present in compound indigestion remedies. It should be used with care in patients on saltrestricted intake (e.g. patients with hypertension). To be used for short-term periods.
Systemic antacids calcium-containing salts These can induce rebound acid secretion and so should not be used for prolonged periods. Prolonged high doses may cause hypercalcaemia and alkalosis.
Non-systemic antacids These are antacids that are not absorbed. They include aluminium salts, magnesium salts and aluminium magnesium compound preprations (mixture). Side-effects Aluminium: constipation, phosphate depletion Magnesium: diarrhoea, hypermagnesaemia Calcium carbonate: acid rebound, hypercalcaemia, renal calculi Sodium bicarbonate: hypernatraemia, bicarbonate alkalosis.
Factors to consider when choosing an antacid Mechanism of action: systemic or non-systemic Dosage form: liquid preparations more effective than solid formulations Administration and dosage regimen Side-effects Taste: flavour of liquid formulation or chewable tablets Packaging: convenience to carry around Price.
Other active ingredients in combination with antacids Antiflatulents: simeticone (used also in infant colic see Chapter 50), activated charcoal Alginates: protectants against gastro-oesophageal reflux (e.g. aliginic acid). NOTE: Antacids may be used in addition to H2- receptor antagonists or proton pump inhibitors to manage occurrence of symptoms.
H2-receptor antagonists These products are structural analogues of histamine. They act as antagonists to the histamine type 2 recep- tors which are predominantly found in the gastric parietal cells. Examples : cimetidine, ranitidine, famotidine and nizatidine. All have similar effectiveness and all have rapid absorption after oral administration. Cimetidine and ranitidine are primarily metabolised in the liver while famotidine and nizatidine are primarily excreted from the kidneys.
H2-receptor antagonists Side-effects Common: dizziness, fatigue, rash Rare: headache, liver dysfunction, blood disorders, bradycardia, confusion, gynaecomastia (cimetidine).
Drugs interacting with cimetidine Cimetidine binds to the cytochrome P450 enzymes and it may cause clinically significant drug interactions particularly for drugs with a narrow therapeutic index. Examples include: benzodiazepines beta blockers calcium channel blockers imipramine phenytoin theophylline warfarin.
Proton pump inhibitors Proton pump inhibitors act by irreversibly binding to K+/H+ ATPase. They have a prolonged duration of action. Examples include omeprazole, esomperazole, lansoprazole, pantoprazole and rabeprazole. They are used in gastro-oesophageal reflux disease, H. pylori triple therapy eradication programme and acid-nsaid peptic ulcer disease. They are rapidly absorbed after oral administra- tion and are eliminated by hepatic metabolism. Side- effects include diarrhoea, nausea and vomiting, and headache. Dosage frequency: once daily.
Interactions for proton pump inhibitors Proton pump inhibitors bind to P450 enzymes. Clinically significant drug interactions may occur with the following: Antiepileptics omeprazole and esomeprazole: effects of phenytoin may be enhanced Warfarin: possibly enhanced anticoagulant effect.
Prostaglandin analogues Synthetic prostaglandin analogues, such as misoprostol, exhibit antisecretory and protective properties. They promote healing of ulcers and are used to prevent NSAID-associated ulcers. Side-effects: crampy abdominal pain, diarrhoea Contraindication: pregnancy since it may cause miscarriage.
Nocturnal gastric acid suppression Bedtime ranitidine is more effective than bedtime omeprazole on residual nocturnal acid secretion. This is clinically significant for patients taking a proton pump inhibitor twice daily who remain symptomatic during the night.
Acute upper gastrointestinal bleeding Around 50% of cases of acute upper gastrointestinal bleeding are due to peptic ulceration. Stabilisation of blood pressure is required and endoscopy should be planned. In vitro studies suggest that platelet aggregation and blood coagulation are impaired when the ph of gastric fluids is below 6.8. Therefore haemostasis may be promoted by suppressing acid secretion using proton pump inhibitors. Use of intravenous injection or tablets of omeprazole reduces risk of continued bleeding or re-bleeding.
Comparison of H2-receptor antagonists and proton pump inhibitors (PPIs)
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