Peptic Ulcer

Peptic Ulcer

Shedding off inflammatory necrotic tissues from the surface of an organ or tissue is called ulcer. Shedding off inflammatory necrotic tissues from mucosal surface of stomach or duodenum is called peptic ulcer. The peptic ulcer is mainly due to increased secretion of gastric acid, gastric enzyme, inadequate protection of gastric mucosal surface and Gram-negative bacteria Helicobacter pyroli infection.

There are three types of peptic ulcer:

·         Chronic duodenal ulcer

·         Chronic gastric ulcer

·         Zollinger Ellison Syndrome

Aims of Peptic ulcer treatment are

·         Reduction in gastric acid secretion

·         Neutralisation of secreted gastric acid

·         Protection of gastric mucosa

·         Gram-negative Helicobacter eradication

Classification

Following drugs are used in treatment of peptic ulcer

·         Antacids to neutralize gastric acid

·         Gastric acid secretion inhibitors

o   Benzimidazole: Omeprazole, Pantoprazole, Lansoprazole

o   H₂ Receptor Antagonists: Cimetidine, Ranitidine, Famotidine, Roxatidine, Ebrotidine etc

o   M₁ Selective Anticholinergic Drugs: Pirenzepine, Telenzepine

·         Antigastrin agents: Oxethazine, proglumide

·         Ulcer insulators: colloids, bismuth

·         Ulcer healing agents: Prostaglandin, Carbenoxolone

·         Antimicrobial agents: Amoxycillin, Tetracycline, Metronidazole, Clarithromycin.

Gastric Acid Secretion inhibitors: Gastric acid is secreted by parietal cells. It is regulated by acetylcholine, histamine gastrin, and prostaglandin. They act through respective receptors to regulate proton pump and gastric secretion. Acetylcholine, histamine, and gastrin activate proton pump (Also called H⁺/K⁺ ATPase pump). Proton pump activation promotes potassium ion entry into parietal cells and hydrogen ion entry into the gastric lumen from parietal cells by consuming ATP.

Acetylcholine and gastrin increase intracellular calcium level that activates H⁺/K⁺ ATPase enzyme in proton pump to secrete gastric acid. Histamine activates enzyme adenylyl cyclase that converts ATP into cAMP. cAMP activate proton pump to release gastric acid. Prostaglandin blocks adenylyl cyclase that inhibits gastric acid secretion through proton pump.

BENZIMIDAZOLE:

Omeprazole: It is acid labile drug and administered in enteric-coated tablet form to protect it from gastric acid in the stomach. It is rapidly absorbed from the intestine and bound with plasma protein up to 90%. It remains unchanged in blood and transported into parietal cells. It is metabolized into active metabolites by protonation in side parietal cells. Active metabolites form stable (irreversible) sulfide bond with enzyme ATPase enzyme that inhibits secretion of gastric acid through proton pump for approximately 24 hours.

Adverse effects: a Headache, dizziness, diarrhea, skin rashes, leucopenia hypochlorhydria, and secondary hypergastrinemia. Longer use may promote the growth of Helicobacter pyroli.

Therapeutic uses: Omeprazole is used to treat following disease conditions

·         Peptic Ulcer: It is used to treat the active duodenal ulcer and active gastric ulcer. It is more effective than H₂ antagonists. It should not be used for more than 8 weeks continuously because it may cause achlorhydria. Duodenal ulcer requires 2 to 4 weeks treatment. Gastric ulcer requires 4 to 8 weeks treatment

·         Zollinger Ellison Syndrome: Omeprazole is drug of choice to treat Zollinger Ellison Syndrome

·         Reflux oesophagitis: Omeprazole is more effective to treat Reflux oesophagitis than H₂ antagonists.

Lansoprazole and Pantoprazole have similar effects as omeprazole with short duration of action.

H₂ Receptor Antagonists: H₂ Receptors are found in various organs such as the stomach, bronchial smooth muscles, cardiovascular systems etc. H₂ Receptor antagonists in therapeutic dose usually affect the only stomach. They are competitive H₂ Receptor antagonist of histamine. They inhibit histamine reversibly. They block gastric acid secretion induced by histamine and gastrin. They also antagonize gastric acid secretion induced by cholinergic agonists having muscarinic effects up to some extent. They act by reducing cAMP concentration up to 80% through H₂ Receptors to reduce secretion of gastric acid. They also reduce secretion of pepsin and intrinsic factors.

Cimetidine, Ranitidine, Famotidine, and Nizatidine are used to treat peptic ulcer. They are H₂ Receptor Antagonists. Nizatidine has highest bioavailability and potency. Nizatidine has half-life about 75 minutes while others have half-life about 2 to 4 hours. They all have a short half-life. They are all tolerated by the body. Thus they are administered in large dose.once in a day. They efficiently block basal, food stimulated and nocturnal gastric acid secretion after a single dose.

Cimetidine:  It is not recommended due to the availability of better drugs to treat peptic ulcer. It has following demerits.

·         It inhibits the hepatic microsomal enzyme. This prolongs the duration of action of other drugs, administered with cimetidine.

·         Short duration of action

·         Adverse effects like restlessness, delirium, confusion, convulsion, coma.

Ranitidine: It is more potent than cimetidine. It does not block hepatic microsomal enzyme secretion and has little CNS effect. It inhibits gastric alcohol dehydrogenase. Thus it increases alcohol concentration in blood upon oral administration.

Nizatidine: It has the highest bioavailability and more potent among all four drugs. It is excreted unchanged in urine.

Roxatidine and Famotidine: It is more potent than nizatidine. Food or antacids do not affect its absorption in GIT.

Uses:

·         Peptic Ulcer: They are most preferred first-line therapy to treat peptic ulcer. Treat require 4 to 8 weeks. In most cases, 80% healing occurs after completion of doses. Then it is continued for longer duration in dose schedule one tablet daily. This prevents further deterioration.

·         Gastritis: Gastric secretion increases during stress. That may precipitate gastritis and stress ulcer in stomach or duodenum. H₂ receptor antagonists are very effective to treat gastritis and stress ulcer.

·         Zollinger Ellison Syndrome: Surgery is most effective to control Zollinger Ellison syndrome. The second choice is omeprazole or Lansoprazole. However, H₂ receptor antagonists are also very effective.

·        Dyspepsia (Indigestion): Dyspepsia without ulcer is a complicated situation. H₂ receptor antagonists are effective to manage dyspepsia.

·      Reflux oesophagitis: Omeprazole is a preferred drug. H₂ receptor antagonists are less effective but they show improving the result.

·       Heartburn (Gastroesophageal reflux): H₂ receptor antagonists are preferred to treat heartburn but are more effective.

·        

      Pruritis: H₁ receptor antagonists are used for treating pruritis. H₂ receptor antagonists are administered as an adjuvant with H₁ receptor antagonists.

ANTICHOLINERGICS: Cholinergic system increases GIT motility and gastric secretion through muscarinic receptors. Anticholinergic drugs with selective muscarinic receptor blocker effect are used to treat peptic ulcer. Selective M₁ receptor antagonist action and little M2, M3 and M₄ receptor antagonist activity are used. Usually, they are preferred as an adjuvant to treat peptic ulcer and Zollinger Ellison syndrome due to its low effectiveness to reduce basal acid secretion and stimulated acid secretion.

ANTIGASTRIN AGENTS:  They have structural similarity with gastrin. They competitively block gastrin receptors. They are almost equally effective as H₂ receptor blockers.

ULCER INSULATOR: They are mucosal protective agents also called cytoprotective. They promote ulcer healing, reduce inflammation and prevent mucosal injury.

Sucralfate: It is aluminum hydroxide and sucrose octasulfate complex. It forms a viscous yellow-white gel at pH below 4 by polymerization. Gel binds to a protein, a glycoprotein of gastric mucosa and sticks with ulcer surface. It covers ulcer surface and acts as a physical barrier. Thus, it protects ulcer surface from the further attack of gastric acid and pepsin. Gel remains on ulcer surface for almost 5 to 6 hours. Gastric food contents and antacid do not alter its surface adhesion effect. But it should not be administered with antacids because its polymerization occurs at acidic pH.

It also stimulates bicarbonate, mucus and prostaglandin release. This makes pepsin ineffective. By these mechanisms, it heals the peptic ulcer. It is used for a long duration to block further deterioration in peptic ulcer condition and its recurrence.

Adverse effects: It is well tolerated and has little absorption from GIT. Thus they have a very low adverse effect. Constipation, mouth dryness, diarrhea, nausea, dizziness, and pruritis may occur.

Bismuth Compounds: Colloidal bismuth preparation heals peptic ulcer very effectively. Bismuth compounds increase mucus secretion and inhibit pepsin activity, interact with necrotic mucosal tissue protein, coat necrotic ulcer crater to protect it from gastric acid and pepsin. It also acts as an antibacterial agent by Helicobacter pylori detachment and lysis. Bismuth compounds can eradicate about 80% H. Pylori. Amoxycillin, Metronidazole, and bismuth compounds are used for 1 to 4 weeks for complete eradication of H.pylori. Bismuth compounds do not have antacid property.

Prostaglandins: Gastric mucosa secretes prostaglandins E₁ and E_2. These prostaglandins secretion inhibit gastric acid release. Thus prostaglandin deficiency promotes ulceration in GIT. Prostaglandins produce following actions in GIT

·         Decrease cAMP level in parietal cells to decrease gastric acid secretion

·         Increase gastric mucous secretion

·         Increase mucosal blood flow.

·         All these increase gastric mucosal barrier strength.

Peptic ulcer due to excessive use of NSAIDs is treated by prostaglandins synthetic analog very efficiently. H₂ antagonists are more effective than prostaglandins to treat an acute peptic ulcer. Smoking inhibits prostaglandin synthesis thus smoking promote peptic ulcer. Prostaglandin synthetic analogs reverse imbalance of prostaglandins due to smoking. Thus they are effective to treat peptic ulcer in smokers.\Prostaglandins produce uterine contraction thus they are contraindicated during pregnancy. Ex. Misoprostol, Enprostil.

Antacids: Antacids are acid neutralizing agents that act as weak base. They neutralize gastric acid in the gastric lumen. However, they are not able to neutralize continuously secreted gastric acid in normal dose. But they are frequently used to manage peptic ulcer due to following reasons:

·         Antacid increase pH of the gastric acid lumen. Pepsin becomes ineffective at pH 4.

·         Antacids reduce H. Pylori colonization.

·         Antacids increase prostaglandins release in gastric mucosa.

Their gastric neutralizing capacity depends upon stomach condition. They are more effective in stomach containing food than an empty stomach. Food content delays emptying time of antacids. This increase antacid stays in the stomach and thereby their effectiveness. Antacids are used alone or in combination.

Classification: Antacids vary in their composition, acid neutralizing capacity, sodium content, palatability, price and their effects.Antacids are classified into following two classes depending upon their mode of action

·         Systemic Antacids:  Sodium bicarbonate

·      Non-Systemic Antacids:

o   Calcium-Containing Antacids

o   Aluminium Containing Antacids

o   Magnesium Containing Antacids

Antacids are divided into following two groups, depending upon the rate of absorption:

·         Fast Acting Antacids: Sodium bicarbonate, Magnesium oxide, Magnesium hydroxide, Magnesium carbonate

·         Slow Acting Antacids: Aluminium Hydroxide, Magnesium Trisilicate.

Sodium bicarbonate: It has a short duration of action, rapid action and highest potency as an antacid. But it is not prescribed and preferred due to following reasons:

·         Rebound hyperacidity

·         Systemic alkalosis

·         Belching due to carbon dioxide release after neutralization of gastric acid

·         Appearance of CHF, hypertension, and edema due to high sodium content in sodium bicarbonate and its absorption

·         Development of renal disease

Aluminium hydroxide: It stimulates mucous secretion in GIT that enhances gastric mucosal barrier strength to resist gastric lumen acidity. It also inactivates pepsin by rising gastric pH. It is weak, slow acting antacid. It decreases peristaltic movement and produces constipation. Aluminium is a toxic element. Its absorption produces encephalopathy (permanent brain injury), osteodystrophy (defective bone development), proximal myopathy (muscle disease, improper function of muscle) and renal impairment.

Magnesium compound: Magnesium compounds produce a laxative effect. Magnesium hydroxide is most fast-acting antacid. Magnesium trisilicate is slow acting with poor antacid activity. It reacts with gastric acid to produce silicon dioxide hydrate that absorbs pepsin.

Calcium carbonate: It is fast acting antacid. It neutralizes gastric acid and releases carbon dioxide with calcium. The release of carbon dioxide produces flatulence abdominal discomfort and belching. The release of calcium stimulates gastrin secretion that causes rebound hyperacidity. Absorption of calcium from GIT produces hypercalcemia.

  Administration of calcium carbonate with sodium bicarbonate and milk produces milk-alkali syndrome. Symptoms of the milk-alkali syndrome are hypercalcemia, renal calculi, and renal impairment. Calcium and protein present in milk actually stimulate gastric secretion of gastrin and gastric acid.

Combination Antacids: Various antacid combinations are available in the market. Among them, only a few combinations have some advantages.

·         Combination of rapid-acting magnesium hydroxide and slow acting aluminum hydroxide

·         Magaldrate : Magaldrate is hydroxymagnesium aluminate complex.[Mg(OH)₂ and Al(OH)₂]. It is poorly absorbed thus provide sustained antacid action.

·         Addition of simethicone and methyl polysiloxane. They have antiflatulence action.

·         Addition of seaweeds alginate. It makes mucous viscous. Viscous mucous makes a coat on GIT mucosa. It is most effective in a patient suffering from gastroesophageal reflux.

Uses:

·         Peptic ulcer: Antacids neutralize gastric acid. But gastric acid complete neutralization requires a high and frequent dose of antacid. This will be inconvenient and impractical. Thus antacids are used as an adjuvant to H₂ receptor blockers in the treatment of peptic ulcer.

·         Gastroesophageal reflux: Antacids increase gastric pH, improve gastroesophageal sphincter tone to produce relief from acute abdominal pain. Omeprazole, a proton pump inhibitor, is a better choice due to high dose and frequent administration of antacids.

PS: Parietal cells: It is also known as delomorphous cells. It secretes hydrochloric acid and intrinsic factors. It is present in fundus and body of stomach gastric glands.

Zollinger Ellison Syndrome: Presence of a tumor in pancreas or duodenum. There is too much secretion of gastric acid due to increase in secretion of gastrin.

Reflux Oesophagitis: Upward movement of acid contents from the stomach into the esophagus is called reflux or acid reflux. Acid reflux is also called heartburn i.e. painful burning sensation in upper abdomen or chest and sometimes in the back also. Reflux oesophagitis is inflammation esophagus lining due to acid reflux.

Basal Gastric acid: Stomach continuously secretes basal gastric acid. It has pH 0.8 that get diluted in stomach lumen.

Nocturnal Gastric Acid: Appearance of gastric acid in stomach lumen to maintain pH below 4 for more than one hour during night time is called nocturnal gastric acid or nocturnal gastric acid breakthrough.

Dyspepsia: Painful and disturbed digestion accompanied by nausea, vomiting, heartburn, bloating and stomach discomfort.

Crater: Roughly Circular Depression.  

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