DYSPEPSIA
Definition: It is a common symptom reflecting GIT disturbance (Fig. 10.1.1). Patient complains of vague feeling of discomfort in upper abdomen. There may be pain or burning sensation, feeling of fullness of the abdomen (usually described by the patient as collection of the gases in the stomach- flatulent dyspepsia), There may be belching and eructation. Patient may feel relief after belching. Dyspepsia may be because of irritation of the stomach by the disease process or by administration of the drugs. It may also be because of collection of gases because of habit of air-swallowing (aerophagy). There may be hypersecretion of gastric acid.
Treatment of Dyspepsia
Drugs provide symptomatic relief. Following drugs may bring some benefit:
Carminatives:
- These are the substances that cause mild stimulation of the gastrointestinal tract and cause relaxation of the sphincters. When sphincter at the cardiac end of the stomach relaxes, the gases escape through the esophagus and patient feels relief. Antispasmodic action may also be helpful to relieve the pain due to spasm. Carminatives give some sensation of warmth and that is liked by the patient.
- Cinnamon, cardamom, ginger, cumin seeds, caraway, dill, pepper, asafoetida, are the examples of the substances having carminative property. Almost all these substances are used in Indian kitchen. They are described as condiments or spices. Mint and CO2 also have carminative action.
- Carminative mixture: A compounded preparation is having the following formulation:Sodium bicarbonate1 gTincture cardamom compound2 mlSimple Syrup2 mlWater up to30 ml
This mixture is usually prescribed after meals. 30 ml is the dose which is repeated three times a day. If given before meals, it may serve as appetizer.
Other carminatives available:
- – Dimethicone: Tab 25 mg
- – Methylpolysiloxane: 25 mg/10 ml.
Digestive Enzyme Preparations
- Amylase, trypsin, lipase (pancreatin), diastase, etc.
- These will help ONLY if there is deficiency of these enzymes. It is NOT very common or is not the cause of dyspepsia in all cases.
Adsorbents and Defoaming Agents
- Activated charcoal adsorbs the gases. Simethicone acts as surface tension reducing agent (result in collapsing of small air bubbles).
- These compounds may have value as an adjuvant.
Antacids and Agents Reducing Acid Secretion
- These agents will be helpful if increased gastric acid secretion is the cause of dyspepsia.
Prokinetic Agents
- These agents will increase gastric motility and would hurry the passage of food from stomach onwards. If gastric stasis (e.g. diabetic gastro-paresis) is the reason for dyspepsia these agents would be useful.
PEPTIC ULCER
- Acid-peptic disease is common in the present days that are full of tension and anxiety. Peptic ulcer may result from increased acid secretion or impaired defense mechanism of gastric mucosa or both (see Fig. 10.1.2).
- It is thought to result from an imbalance between acid-pepsin secretion and mucosal, bicarbonate and prostaglandins (Fig. 10.1.2).
- Gastric acid secretion is regulated by three pathways–vagus (ACh), gastrin and local release of histamine–each acting through its own receptors. These activate H+ K+ ATPase (proton pump) on the parietal cells resulting in the secretion of H+ into the gastric lumen where it combines with CI− (drawn from plasma) and HCl is secreted (Fig. 10.1.3).
- Acetycholine and gastrin act both directly on the parietal cells and indirectly by releasing histamine from the enterochromaffin cells.
- Histamine acts through H2 receptors on the parietal cells while acetylcholine through M1 muscarinic and gastrin through G receptors (Fig. 10.1.3).
- AIM of the treatment should be to control the pain, to help in healing of the ulcer and to prevent complications like bleeding and perforation and prevent relapse.
Classification
- Drugs that neutralize gastric acid Antacids; Al(OH)3, MgOH2.
- Drugs that reduce gastric acid secretion.
- H2 receptor blockers – Cimetidine, Ranitidine, Famotidine, Roxatidine, Nizatidine.
- Proton pump inhibitors – Omeprazole, Lansoprazole, Pentoprazole
- Muscarinic antagonists – Pirenzepine.
- Ulcer protectives: Sucralfate, Bismuth compounds.
- Other drugs: Carbenoxolone, Prostaglandin (analogues, i.e. misoprostole.
- Anti H. Pylori drugs.
ANTACIDS
- Antacids are basic substances which when given orally, neutralizes the gastric acid and raise the pH of gastric contents. Peptic activity is also reduced, as pepsin is active only above pH 4.
- Antacids are of 2 types:
- Systemic: Sodium bicarbonate
- Nonsystemic: Aluminium hydroxide, Magnesium trisilicate, Magnesium hydroxide, Calcium carbonate.
Systemic Antacids
- Sodium bicarbonate is rapid but short-acting. CO2 that is released in the stomach escapes as eructation.
- It gets absorbed from the intestines leading to systemic alkalosis. There is ‘rebound’ hyperacidity as gastrin levels increases due to raised gastric pH. Sodium load may increase.
- It is not preferred because of the above disadvantages.
- Sodium bicarbonate is used with other antacids in peptic ulcer. Other uses are to alkalinise the urine in poisoning and to treat metabolic acidosis.
Non-systemic Antacids
- Non-systemic antacids are insoluble compounds that react in the stomach with HCl to form a chloride salt and water. They are not absorbed.
- Aluminium hydroxide [Al (OH)3] is slow acting. Food further slows it's neutralizing capacity. It is also an astringent and demulcent – forms a protective coating over the ulcers.
- The aluminium ions relax the smooth muscles resulting in delayed gastric emptying and constipation. Aluminium hydroxide binds phosphate and prevents its absorption resulting in hypophosphatemia on prolonged use.
- Magnesium salts [Mg (OH)2] The action is quick and prolonged. Rebound acidity is mild.
- Magnesium salts are osmotic purgatives and the dose used as antacids may cause mild diarrhea.
- Calcium carbonate (CaCO3) acts quickly and has prolonged action but liberates CO2 which may cause discomfort. It may also cause constipation and hypercalcemia.
Antacid combinations are given to obtain maximum effects with least adverse effects as follows:
- Quick and prolonged effect – Fast-acting [Mg(OH2)] and slow acting [AI(OH)3] are combined.
- Neutralising side effects – Magnesium salts have a laxative effect while aluminium salts are constipating-combination neutralizes each others side effects.
- Gastric emptying – Magnesium salts hasten while aluminium salts delay gastric emptying.
Note: All antacid tablets should be chewed and swallowed with 2 glasses of water as they do not disintegrate well in the stomach. Gels are more effective than tablets. One dose given 1 hr after food neutralizes the acid. (for 2 hours)
As per according to katzung basic and chemical pharmacology, 10th edition antacid also promotes mucosal defence mechanisms through stimulation of mucosal prostaglandin production.
Uses: Antacids are used as adjuvant in hyperacidity, peptic ulcer and reflux esophagitis.
Drug interactions
- Antacids form complexes with iron, tetracyclines, digoxin, ranitidine, fluoroquinolones, sulfonamides and antimuscarinic drugs.
- To avoid these, antacids should be taken 2 hours before or 2 hours after other drugs.
H2 RECEPTOR BLOCKERS
- Cimetidine, ranitidine, famotidine, roxatidine.
- These drugs competitively inhibit the action of histamine on H2 receptors and thereby reduce gastric secretion. Both volume and acidity of basal, nocturnal and food induced secretion are reduced.
- They can cause 90% reduction in gastric secretion by a single dose. Gastrin induced HCl secretion and pepsin is also reduced. These actions hasten the healing of peptic ulcers.
- Pharmacokinetics: H2 blockers are well-absorbed. Cimetidine acts for 5–8 hours, ranitidine and famotidine for 12 hours.
Adverse effects: The H2 blockers are well-tolerated. Their adverse effects are discussed with individual agents.
Cimetidine
- It has antiandrogenic actions, it increases plasma prolactin levels and inhibits estrogen metabolism in the liver.
- Headache, dizziness, rashes and diarrhea can result.
- On prolonged use it may result in gynecomastia, impotence and loss of libido.
- CNS effects include confusion, delirium and hallucinations in the elderly.
- Cimetidine inhibits microsomal enzymes and interferes with the metabolism of many drugs.
Ranitidine
- It is the preferred H2 blocker as it has several advantages over cimetidine.
- Ranitidine is more potent, longer acting, has no antiandrogenic effects, no CNS effects as it does not cross BBB and does not inhibit microsomal enzymes significantly.
- Only adverse effects are headache and dizziness.
Famotidine
- It is similar to but more potent than ranitidine.
- Headache and rashes can occur.
- More suitable for ZE syndrome.
Roxatidine. It is similar to ranitidine but is more potent and longer-acting.
Loxatidine. Newer drug. Completely block HCl secretion.
Uses of H2 blockers
- H2 blockers are used in the treatment of peptic ulcer, gastritis, reflux esophagitis, and as preanesthetic medication and to prevent damage if aspiration pneumonia occurs during surgery.
- Ranitidine is the most preferred. It is given for 4–8 weeks in peptic ulcers. It may be continued for 6 months to prevent recurrence.
PROTON PUMP INHIBITORS
Omeprazole
- The parietal cells of the stomach secrete H+ with the help of an enzyme H+ K+ ATPase (proton pump) present in the plasma membrane.
- This is the final step in gastric acid secretion due to any stimuli. Proton pump inhibitors specifically inhibit this enzyme and thereby inhibit gastric secretion.
- Omeprazole is a prodrug, gets activated in the acidic environment of the stomach and a single dose can totally inhibit gastric secretion.
- Acid secretion starts only after new H+ K+ ATPase enzyme is synthesized. Ulcer heals rapidly even in resistant cases.
Uses
- Omeprazole is used in peptic ulcers and severe gastroesophageal reflux diseases that is not responding to H2 blockers. (GERD)
- Zollinger - Ellison (ZE) syndroms.
- Ulcers heal fast and pain is relieved. It is given for 4–8 weeks.
- It also inhibits the growth of H. Pylori, directly and by ↑PH.
Adverse effects
- Omeprazole is well-tolerated.
- Prolonged acid suppression may allow bacterial over growth in the stomach. Carcinoid tumors are reported in rats but not in humans.
- Dizziness, headache, nausea and rashes are rare.
Lansoprazole: It is similar to omeprazole but is longer-acting.
- Pentoprazole, Rabeprazole and Esmoprazole are the newer agents.
Anticholinergics
- Though atropine reduces gastric secretion, the dose needed results in several adverse effects.
- A derivative of atropine—pirenzepine selectively blocks gastric M1 receptors and inhibits gastric secretion by 40–50% without significant side effects.
- It also inhibits the secretion of gastrin, mucous and bicarbonate. It is used as an adjuvant.
ULCER PROTECTIVES (Table 10.1.1)
Sucralfate
- In acidic medium (pH < 4), sucralfate polymerizes to from a sticky, viscid gel which firmly adheres to the base of the ulcers.
- It remains there for over 6 hours acting as a physical barrier and prevents contact of mucosa and submucosa with acid and pepsin.
- It also stimulates the PG synthesis in gastric mucosa. It thus promotes healing by protecting the ulcer. Sucralfate is not absorbed and is well-tolerated.
- One tablet is given 1 hr before each meal and one at bed time for 4–8 weeks and then 1 gram BD is continued for 6 months to prevent recurrence.
- Side effects are rare and include constipation and dryness of mouth.
Drug interactions
- – Sucralfate needs acidic pH for activation. Hence antacids should not be given with it.
- – Sucralfate absorbs and interferes with the absorption of tetracyclines, digoxin, phenytoin and cimetidine.
Bismuth salts
- Colloidal bismuth sub-citrate on oral administration chelate proteins in the ulcer base and forms a protective coating over the gastric mucosa.
- It also inhibits the growth of H. pylori on gastric mucosa and stimulates the mucous production and PG synthesis.
- By these actions it promotes ulcer healing in 4–8 weeks. It may cause constipation and black stools.
OTHER DRUGS
Carbenoxolone
- It is a steroid like compound obtained form glycyrrhizic acid found in the root of liquorice.
- On ingestion, it alters the composition of mucous so that it is more viscid and adheres to gastric mucosa to protect the ulcer base.
- It also inhibits pepsin activity and prolongs the life of PGs. Because of its steroid like effects, it causes salt and water retention. It is therefore not preferred.
Prostaglandin analogues
- PGE2 and PGI2 synthesized by the gastric mucosa inhibits gastric secretion, enhances mucous production and exerts a cytoprotective effect.
- PG analogs misoprostol and enprostil given orally are of special value in preventing drug induced (e.g. NSAIDs) gastric ulceration. Diarrhea and muscle cramps are common.
Treatment of H. pylori Infection
- – The gram negative bacterium H. pylori is adapted to living in the stomach.
- – Infection with H. pylori is associated with gastrodeodenal disease including gastritis and peptic ulcer. It is also thought to be responsible for recurrence of peptic ulcer disease.
- – Eradication of H. pylori along with drugs that reduce acid secretion has shown to reduce the relapse rate.
Various combination regimens are tried with clarithromycin, amoxicillin or tetracycline; metronidazole and omeprazole for 1–2 weeks.
Other drugs: For eradication H. pylori : Metronidazole, Tetracycline, Amoxicillin, etc.
Triple drug regimen is preferred:
- Colloidal bismuth subcitrate 120 mg qid + Tetracycline 500 mg qid/Amoxicillin 500 mg tid + Metronidazole 400 mg tid (all for 14 days). Other options are:
- Omeprazole 20 mg bid + Clarithromycin 500 mg bid + Amoxicillin 1 g bid (all for 7 days);
- (ii) Ranitidine 300 mg OD + Amoxicillin 750 mg tid + Metronidazole 500 mg tid x 12 days.
General Measures:
- Diet: regular, frequent and nutritious.
- Food: Avoid any precipitating substance.
- Milk: relieve pain.
- Tea/Coffee/Juices: Take in moderate amount.
- Avoid alcohol and smoking.
- Avoid certain drugs like Aspirin
- Adequate sleep and rest.