Review on Gastrointestinal Disorders and Management Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa

Gastrointestinal Tract Main function is digestion and absorption of food One of the major endocrine systems in the body It has own integrative neuronal network It is the site of many common pathologies Medicines for treating these GI disorders comprise some 8% of all prescriptions Objectives of This Review Physiological control of GI function Pharmacological characteristics of drugs affecting gastric secretion and motility

Gastric Secretion Stomach secretes about 2.5 liters of gastric juice daily Principal secretions are prorennin, pepsinogen, and hydrochloric acid Mucus-secreting cells abound among the surface cells of the gastric mucosa Bicarbonate ions are secreted and are created a gel-like protective barrier that maintains the mucosal surface at a pH of 6-7 in the face of a much more acidic environment (pH 1-2) in the lumen

Gastrointestinal Disorders: Types Gastric acidity Peptic Ulcer Chronic bowel movement Vomiting Gastroesophageal reflux disorder Diarrhea

Gastric Acidity: Causes Gastric acid secretion is a complex, continuous process in which multiple central and peripheral factors contribute to a common endpoint: the secretion of H+ by parietal cells Neuronal (ACh), paracrine (histamine), and endocrine (gastrin) factors all regulate acid secretion

Gastric Defenses Against Acid High concentration of H+ in the gastric lumen requires robust defense mechanisms to protect the esophagus and the stomach One key defense is the secretion of a mucus layer that protects gastric epithelial cells Gastric mucus is soluble when secreted but quickly forms an insoluble gel that coats the mucosal surface of the stomach, slows ion diffusion, and prevents mucosal damage

Gastric Defenses Against Acid, continued….. Alcohol, aspirin, and other drugs that inhibit prostaglandin formation decrease mucus secretion Secretion of bicarbonate ions by superficial gastric epithelial cells also consider as mucosal defense Bicarbonate neutralizes the acid in the region of the mucosal cells, thereby raising pH and preventing acid-mediated damage

Gastric Acidity: Therapies Proton pump inhibitors H2-Receptor antagonists Proton Pump Inhibitors (PPIs) Inhibitors of the gastric H+, K+-ATPase (proton pump) Diminish the daily production of acid by 80 to 95% All proton pump inhibitors have equivalent efficacy at comparable doses

How PPIs Work? Bind to the proton pump of the parietal cell, thereby suppressing secretion of hydrogen ions into the gastric lumen At the parietal cells irreversibly inactivate pump molecule Acid secretion resumes only after new pump molecules are synthesized

Types of PPIs Five classes of PPIs are available: Omeprazole (PRILOSEC) Esomeprazole (NEXIUM) Lansoprazole (PREVACID) Rabeprazole (ACIPHEX) Pantoprazole (PROTONIX)

PPIs: Actions Prodrugs with an acid-resistant enteric coating to protect them from premature degradation by gastric acid. The coating is removed in the alkaline duodenum, and it is absorbed and transported to the parietal cell canaliculus At parietal cells, it is converted to the active form, which reacts with the proton pump, forming a stable covalent bond Takes ~18 hours for the enzyme to be resynthesized At standard doses, all PPIs inhibit both basal and stimulated gastric acid secretion by more than 90 %

PPIs: Pharmacokinetics Delayed-release formulations and are effective orally Some are also available for intravenous injection Metabolites are excreted in urine and feces PPIs: Adverse Effects Omeprazole inhibits the metabolism of warfarin, phenytoin, diazepam, and cyclosporine Prolonged therapy may result in low vitamin B12, because acid is required for its absorption

H2-Receptor Antagonists Inhibit acid production by reversibly competing with histamine for binding to H2 receptors of parietal cells Less potent than PPI but still suppress 24-hour gastric acid secretion by about 70% Types of H2-Receptor Antagonists Four classes of H2-receptor antagonists are available: Cimetidine Ranitidine Famotidine Nizatidine

H2-Receptor Antagonists: Actions Act selectively on H2 receptors in the stomach, blood vessels, and other sites Competitive antagonists of histamine and are fully reversible Completely inhibit gastric acid secretion induced by histamine or gastrin

H2-Receptor Antagonists: Pharmacokinetics Given orally, distribute widely throughout the body Excreted mainly in the urine Approximately 30% of a dose is slowly inactivated by the liver's microsomal mixed-function oxygenase system Dosage must be decreased in hepatic or renal failure H2-Receptor Antagonists: Adverse Effects Side effects of cemetidine are headache, dizziness, diarrhea, and muscular pain Central nervous system effects (confusion, hallucinations) may occur primarily in elderly patients

Peptic Ulcer: Treatments Peptic Ulcer: Causes Infection with gram-negative Helicobacter pylori Nonsteroidal anti-inflammatory drug (NSAID) use Increased hydrochloric acid secretion Inadequate mucosal defense against gastric acid Peptic Ulcer: Treatments Proton pump inhibitors H2–Histamine receptor antagonists Antimicrobial agents Antimuscarinic agents Antacids Mucosal protective agents

Antimicrobial Agents Therapy for patients with peptic ulcer disease who are infected with H. pylori requires antimicrobial treatment Successful eradication of H. pylori is possible with various combinations of antimicrobial drugs Triple therapy PPI + metronidazole + clarithromycin PPI+ amoxicillin + clarithromycin Quadruple therapy Bismuth subsalicylate + metronidazole + tetracycline + PPI

Antimuscarinic Agents Muscarinic receptor stimulation increases gastrointestinal motility and secretory activity A cholinergic antagonist, such as dicyclomine, can be used in peptic ulcer disease It has side effects: cardiac arrhythmias dry mouth constipation urinary retention

Antacids Antacids are weak bases that react with gastric acid to form water and a salt, thereby diminishing gastric acidity The acid-neutralizing ability depends on its capacity to neutralize gastric HCl and on whether the stomach is full or empty Commonly used antacids are aluminum hydroxide or magnesium hydroxide, either alone or in combination Calcium carbonate [CaCO3] reacts with HCl to form CO2 and CaCl2 and is a commonly used preparation

Antacids: Adverse Effects Aluminum hydroxide tends to be constipating, and magnesium hydroxide tends to produce diarrhea The binding of phosphate by aluminum-containing antacids can lead to hypophosphatemia Excessive intake of calcium carbonate along with calcium foods can result in hypercalcemia

Mucosal Protective Agents: Sucralfate This complex of aluminum hydroxide and sulfated sucrose binds to proteins of mucosa By forming complex gels with epithelial cells, it creates a physical barrier that impairs diffusion of HCl and prevents degradation of mucus by pepsin and acid Heals duodenal ulcers and is used in long-term maintenance therapy to prevent their recurrence Bismuth Subsalicylate Effectively heal peptic ulcers In addition to their antimicrobial actions, they inhibit the activity of pepsin, increase secretion of mucus

MOA of Different Agents for the Treatment of Peptic Ulcer

Agents for the Treatment of Peptic Ulcer: Summary

Peptic Ulcer: Classification Based on the location, peptic ulcers are 3 types: Gastric ulcer Stomach Duodenal ulcer Duodenum Esophageal ulcer Esophagus

Gastroesophageal Reflux Disease (GERD) PPIs are more effective than H2-receptor antagonists Healing rates after 4-8 weeks of therapy with PPIs are approximately 80% -90%, while the healing rates with H2-receptor antagonists are 50%-75% Therapy Includes: Proton pump inhibitors H2-receptor antagonists

Vomiting A physical event that results in forceful evacuation of gastric contents through the mouth It is often preceded by nausea Can be a valuable physiological response to the ingestion of a toxic substance An unwanted side effect of many clinically used drugs Occurs in motion sickness and during early pregnancy, and as well as bacterial and viral infections

Vomiting: Treatments with Antiemetic Drugs Antiemetics represent a variety of classes and offer a range of efficacies Anticholinergic drugs, especially the muscarinic receptor antagonist, scopolamine, and H1-receptor antagonists are very useful in motion Major categories of drugs used to control chemotherapy -induced nausea and vomiting include the following: 5-HT3 receptor blockers: Ondansetron, and dolasetron Phenothiazines: Prochlorperazine

Vomiting: Role of Emetics Induced emesis is the preferred means of emptying the stomach in awake patients who have ingested a toxic substance or have recently taken a drug overdose The most commonly used emetics are ipecac and apomorphine Emesis should not be induced if the patient has central nervous system depression

Inflammatory Bowel Disease (IBD) Causes significant GI symptoms that include diarrhea, abdominal pain, bleeding and weight loss IBD is divided into two major subtypes: Ulcerative colitis Ulcerative colitis is characterized by confluent mucosal inflammation of the colon Crohn's disease Crohn's disease is characterized by transmural inflammation of the gastrointestinal tract Inflammatory Bowel Disease: Treatments Therapy for mild to moderate ulcerative colitis generally involves mesalamine (5-aminosalicylic acid) Glucocorticoids are also useful on the inflammatory response

Diarrhea Diarrhea is the frequent passage of liquid feces, accompanied by abdominal cramps and sometimes nausea and vomiting Increased motility of the GI tract and decreased absorption of fluid are major factors in diarrhea A physiological mechanism for rapidly ridding the gut of poisonous or irritating substances There are numerous causes Underlying disease, infection, toxins and even anxiety May also arise as a side effect of drug or radiation therapy One of the principal causes of death in malnourished infants

Diarrhea: Mechanisms Diarrhea: Treatments During an episode of diarrhea, there is an increase in the motility of the GI tract, accompanied by an increased secretion coupled with a decreased absorption of fluid, which leads to a loss of electrolytes and water Diarrhea: Treatments There are three approaches to the treatment of severe acute diarrhea: maintenance of fluid and electrolyte balance use of anti-infective agents use of antidiarrhoeal agents

Diarrheal Agents

Study Questions A 45-year-old woman is distressed by the dissolution of her marriage. She has been drinking heavily and overeating. She complains of persistent heartburn and an unpleasant, acid-like taste in her mouth. The clinician suspects gastrointestinal reflux disease and advises her to raise the head of her bed 6 to 8 inches, to avoid alcohol, and to eat smaller meals. Two weeks later, she returns and says the symptoms have subsided slightly but still are a concern. The clinician prescribes: A. Aluminum hydroxide. B. Dicyclomine. C. Alprazolam. D. Esomeprazole.

A couple celebrating their 25th wedding anniversary is given a trip to Lakshadeep. Due to past experiences while traveling, they ask their doctor to prescribe an agent for diarrhea. Which of the following would be effective? A. Omeprazole. B. Loperamide. C. Famotidine. D. Lorazepam.

While taking a NSAID for arthritis, a 65-year-old man developed a gastric ulcer. He was prescribed cimetidine for 8 weeks. This drug binds a receptor located where? A. Nucleus B. Nucleolus C. Cytoplasm D. Cell membrane E. Cell walls

A 20-year-old woman goes to the emergency department, stating that within the past hour she ingested “a handful of sleeping pills.” She is still awake. Which of the following drugs can be given to induce vomiting? A. Ipecac B. Morphine C. Promethazine D. Ondansetron