GASTROINTESTINAL TRACT ASSOCIATED DISORDER

• GASTROINTESTINAL TRACT ASSOCIATED DISORDER:
• Acid-peptic diseases

  Disorders in which gastric acid and pepsin are necessary, but usually not sufficient, pathogenic factors
• Gastric acid and pepsin

  • Normally do not produce damage or symptoms because of intrinsic defense mechanisms
  • If protective barriers fail and reflux occurs, dyspepsia and/or erosive esophagitis may result
• Gastric mucosa defenses

  Mucus and bicarbonate, stimulated by the local generation of prostaglandins, protect the gastric mucosa
• If these defenses are disrupted, a gastric or duodenal ulcer may form
• Treatment and prevention of acid-related disorders

  Accomplished either by decreasing the level of gastric acidity or by enhancing mucosal protection
• The appreciation that an infectious agent, Helicobacter pylori, plays a key role in the pathogenesis of acid-peptic diseases has stimulated new approaches to prevention and therapy
• Gastric acid secretion

  1. Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors regulate acid secretion

  2. Their specific receptors (M3, H2, and CCK2 receptors, respectively) are on the basolateral membrane of parietal cells

  3. The H2 receptor is a GPCR that activates the Gs–adenylylcyclase– cyclic AMP–PKA pathway

  4. ACh and gastrin signal through GPCRs that couple to the Gq–PLC-IP3–Ca2+ pathway in parietal cells

  5. In parietal cells, the cyclic AMP and the Ca2+- dependent pathways activate H+,K+-ATPase (the proton pump), which exchanges hydrogen and potassium ions across the parietal cell membrane
• Gastric lumen H+ concentration

  • Extremely high, requires robust defense mechanisms to protect the esophagus and the stomach
• Primary esophageal defense

  Lower esophageal sphincter, which prevents reflux of acidic gastric contents into the esophagus
• Gastric mucosal defenses

  • Secretion of a mucus layer that protects gastric epithelial cells
  • Secretion of bicarbonate ions by superficial gastric epithelial cells to neutralize acid and prevent damage
• H2-receptor antagonists

  Inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells
• H2-receptor antagonists

  • cimetidine (TAGAMET), ranitidine (ZANTAC), famotidine (PEPCID), and nizatidine (AXID)
• H2-receptor antagonists

  • Less potent than proton pump inhibitors but still suppress 24- hour gastric acid secretion by about 70%
  • Predominantly inhibit basal acid secretion, which accounts for their efficacy in suppressing nocturnal acid secretion
• Antacids

  Largely have been replaced by more effective and convenient drugs, but continue to be used by patients for a variety of indications
• Antacids

  • Sodium bicarbonate effectively neutralizes acid but is very water soluble and rapidly absorbed, posing risks for patients with cardiac or renal failure
  • Calcium carbonate rapidly and effectively neutralizes gastric H+, but can induce rebound acid secretion
  • Combinations of Mg2+ (rapidly reacting) and Al3+ (slowly reacting) hydroxides provide a relatively balanced and sustained neutralizing capacity
• Peptic ulcer disease

  Imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, and other peptides and growth factors) and injurious factors (acid and pepsin)
• Up to 60% of peptic ulcers are associated with H. pylori infection of the stomach
• NSAIDs also are very frequently associated with peptic ulcers (in up to 60% of patients, particularly those with complications such as bleeding)
• Treatment of Helicobacter pylori infection

  Eradication of H. pylori is standard care in patients with gastric or duodenal ulcers, as it almost completely eliminates the risk of ulcer recurrence
• H. pylori eradication regimens

  1. Combination therapy with two or three antibiotics (plus acid-suppressive therapy) is associated with the highest rate of H. pylori eradication

  2. A regimen of 10 to 14 days of treatment appears to be better than shorter treatment regimens

  3. Packaging that combines the daily doses into one convenient unit is available and may improve patient compliance

  4. In areas with a high frequency of resistance to clarithromycin and metronidazole, a 14-day, quadruple-drug regimen (three antibiotics combined with a proton pump inhibitor) generally is effective therapy
• Gastrointestinal motility disorders

  Complex and heterogeneous group of syndromes whose pathophysiology is not completely understood, including achalasia, gastroparesis, and others
• Dopamine-receptor antagonists

  Effective in treating gastrointestinal motility disorders by antagonizing the inhibitory effect of dopamine on myenteric motor neurons
• Disorders of gastrointestinal motility include achalasia (failure of lower esophageal sphincter relaxation and regurgitation), gastroparesis (delayed gastric emptying), myopathic and neuropathic forms of intestinal dysmotility, and others
• These disorders can be congenital, idiopathic, or secondary to systemic diseases (e.g., diabetes mellitus or scleroderma)
• This term also has traditionally (and perhaps inaccurately) included disorders—such as irritable bowel syndrome and non cardiac chest pain—in which disturbances in pain processing or sensory function may be more important than any associated motor patterns
• For most of these disorders, treatment remains empirical and symptom-based, reflecting our ignorance of the specific derangements in patho physiology involved
• Dopamine-Receptor Antagonists

  Dopamine is present in significant amounts in the GI tract and has several inhibitory effects on motility, including reduction of lower esophageal sphincter and intragastric pressures. These effects, which apparently result from suppression of ACh release from myenteric motor neurons, are mediated by D2 dopaminergic receptors. By antagonizing the inhibitory effect of dopamine on myenteric motor neurons, dopamine receptor antagonists are effective as prokinetic agents; they have the additional advantage of relieving nausea and vomiting by antagonism of dopamine receptors in the chemoreceptor trigger zone.
• Dopamine-Receptor Antagonists

  • metoclopramide
  • domperidone
• Metoclopramide

  Metoclopramide (REGLAN) and other substituted benzamides are derivatives of paraaminobenzoic acid and are structurally related to procainamide.
• Mechanism of action of metoclopramide

  • 5-HT4-receptor agonism, vagal and central 5-HT3-antagonism, and possible sensitization of muscarinic receptors on smooth muscle, in addition to dopamine receptor antagonism. Metoclopramide is one of the oldest true prokinetic agents; its administration results in coordinated contractions that enhance transit. Its effects are confined largely to the upper digestive tract, where it increases lower esophageal sphincter tone and stimulates antral and small intestinal contractions. Despite having in vitro effects on the contractility of colonic smooth muscle, metoclopramide has no clinically significant effects on large-bowel motility.
• GI Water and Electrolyte Flux

  Fluid content is the principal determinant of stool volume and consistency; water normally accounts for 70% to 85% of total stool weight. Net stool fluid content reflects a balance between luminal input (ingestion and secretion of water and electrolytes) and output (absorption) along the length of the GI tract. The daily challenge for the gut is to extract water, minerals, and nutrients from the luminal contents, leaving behind a manageable pool of fluid for proper expulsion of waste material via the process of defecation.
• Normally about 8 to 9 liters of fluid enter the small intestine daily from exogenous and endogenous sources. Net absorption of the water occurs in the small intestine in response to osmotic gradients that result from the uptake and secretion of ions and the absorption of nutrients (mainly sugars and amino acids), with only about 1 to 1.5 liters crossing the ileocecal valve. The colon then extracts most of the remaining fluid, leaving about 100 ml of fecal water daily.
• Under normal circumstances, these quantities are well within the range of the total absorptive capacity of the small bowel (about 16 liters) and colon (4 to 5 liters). Neurohumoral mechanisms, pathogens, and drugs can alter these processes, resulting in changes in either secretion or absorption of fluid by the intestinal epithelium. Altered motility also contributes in a general way to this process, as the extent of absorption parallels transit time. With decreased motility and excess fluid removal, feces can become inspissated and impacted, leading to constipation. When the capacity of the colon to absorb fluid is exceeded, diarrhea will occur.