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

2. 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

3. 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

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

5. 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

6. 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

7. 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

8. 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

9. 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

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

11. 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 %

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. MOA of Different Agents for the Treatment of Peptic Ulcer

23. Agents for the Treatment of Peptic Ulcer: Summary

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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. Diarrheal Agents

33. 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.

34. 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.

35. 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

36. 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