Chapter 27:  Gastrointestinal Drugs

Pharmacological Management of Ulcer Disease

• Peptic ulcer: stomach or duodenal mucosal lesion -- acid and pepsin: major pathogenic roles

• Classification of peptic ulcer:

  • Duodenal (DU)

  • Gastric (GU)

• Major causative factor:bacterium Helicobacter pylori

•  Helicobacter pylori: risk factor for:

  • gastric cancer

  • certain types of gastric lymphoma

•  Zollinger-Ellison syndrome {causative agent-gastrin-secreting islet cell tumor (gastrinoma)} -- considered a form of peptic ulcer

•  Ulcer Development:

  • cause by an imbalance between aggressive factors (mainly gastric acid and pepsin) and protective factors (mucosal defenses)

• Gastric mucosa: acid secretion

  • Oxidative phosphorylation dependent secretion by parietal cells.

    • Parietal cells: found in mucosal glands

    • of the body and fundus of the stomach.

  • Regulation of gastric acid secretion-- many factors (chemical, neural, hormonal)

    • Stimulation:

      1. Gastrin-most potent stimulant

      2.  Activation of postganglionic vagal fibers (muscarinic cholinergic parietal cells receptor activation)

      3. Role of histamine:

         • Gastric mucosa contains large amounts of histamine in:

           1. mast cell cytoplasmic granules

           2. enterochromaffin-like cells (ECL)

         • H₂ receptor antagonists competitively inhibit histamine action on H₂ receptors, located on:

           1. gastric parietal cells

           2. cardiac atrial cells

           3. uterine smooth muscle cells

         • H₂ receptor antagonists (cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid)) inhibit:

           1. basal acid secretion

           2. secretion in response to feeding, gastrin, histamine, hypoglycemia, or vagal stimulation

         • Histamine is the most important gastric acid secretion stimulant and is released from enterochromaffin-like cells by gastric and cholinergic activity

      4. Basolateral parietal cells membranes contain receptors for:

         • histamine-- stimulation gastric acid secretion

         • gastrin-- stimulation gastric acid secretion

         • acetylcholine-- stimulation gastric acid secretion

         • prostaglandins --inhibition of gastric acid secretion

         • somatostatin -- inhibition of gastric acid secretion

• Physiological stimulants of gastric acid secretion:

  • Major physiologic stimulus: food intake -- three phases:

    1. cephalic phase

       • gastric acid secretion responds to anticipation of food, sight, smell, taste

    2. gastric phase

       • stimulation of mechanical and chemical gastric wall receptors by luminal contents.

    3. intestinal phase

       • gastrin release (small amount); release of other peptides that stimulate gastric acid secretion

  • Food constituents:

    • Coffee (both caffeine containing and caffeine free) stimulates gastric acid secretion by stimulating gastric release

    • Beer and wine: stimulation of gastric acid secretion

• Physiologic inhibition- gastric acid release:

  • Factors that inhibit gastric acid secretion include:

    • hyperglycemia

    • hypertonic fluids

    • duodenal fat

    • duodenal acid

    • intragastric pH = 3; partial inhibition

    • intragastric pH < or = 1.5; complete blockade of gastrin release

  • Somatostatin effects:

    • Antral mucosal endocrine cells (D cells) contain somatostatin and impinge on nearby gastrin cells and parietal cells.

    • Somatostatin reduces gastrin release thereby reducing gastric acid secretion by:

      1. inhibiting parietal cells secretion

      2. inhibiting histamine release by enterochromaffin-like cells

•  Role of pepsin in peptic ulcer disease:

  • Secreted gastric acid plus effects of pepsin promote tissue injury

  • Gastric acid promotes cleavage of pepsinogen (inactive) to proteolytically-active pepsins

  • Pepsinogen classification:

    • Direct correlation between pepsinogen I serum concentrations and maximal gastric acid secretion

 Pathogenic Factors

• Peptic ulcer disease: an imbalance between aggressive factors (gastric acid and pepsin) and protective factors (gastric mucus, bicarbonate, prostaglandins)

• Helicobacter pylori: a principal role in peptic ulcer pathogenesis

  • H. pylori:

    • causes active, chronic gastritis

    • Bacterial protein products appear damaging

    • Proteases and phospholipases produced by H. pylori degrade glycoprotein-lipid mucus layer complex

    • H. pylori: proinflammatory

  •  Management of H. pylori infection: clinical consequences

    • 15% relapse rate for duodenal ulcer following H. pylori eradication

    • 75% relapse rate for duodenal ulcer following treatment with H₂ receptor blockers only

• Other Pathogenic Factors:

  • possible genetic factor in duodenal ulcer (frequency of GU ulcers -- three times its common in first-degree relatives of DU patients then in the general population; may however, reflect higher rate of H. pylori infection)

  • Cigarette smoking --

    1. increased incidence of DU

    2. decreased therapeutic response

    3. increased mortality rate from DU

• Patients with documented duodenal ulcers (upper GI contrast radiography or endoscopy) -- treat for H. pylori

• Many drugs, usually in combination,are used in management and eradication of H. pylori infection. Drugs include:

  • bismuth compounds

  • amoxicillin

  • tetracycline (Achromycin)

  • clarithromycin (Biaxin)

  •  metronidazole (Flagyl)

  • omeprazole (Prilosec), lansoprazole (Prevacid)

  • H₂ antagonists

• Bismuth compounds

  • Mechanism of Action:

    • cytoprotective effects

    • compounds bind to the ulcer base, stimulating mucus and prostaglandin production

    • antibacterial effect: inhibition of proteolytic, lipolytic, and urease activities

  •  In monotherapy: bismuth compounds eradicate H. pylori in about 20% of patients

  • Bismuth compounds in combination with antibiotics eradicate H. pylori in up to 95% of patients.

•  Most successful protocol: triple therapy

  • bismuth compounds

  • metronidazole (Flagyl)

  • amoxicillin or tetracycline (Achromycin)

    • Triple therapy (two weeks) plus H₂ blocker therapy (six weeks) is also a recommended protocol

    • Further increase in the rate of H. pylori eradication may be accomplished by the addition of omeprazole (Prilosec) to the regimen.

•  Drawbacks of triple therapy:

  • patient compliance (two-week treatment: 200 tablets)

  • Side effects

•  Some Specifc Drug Classes:

  • Antacids

    • Most widely used: mixture of aluminum hydroxide and magnesium hydroxide (neutralizes HCl)

    •  Aluminum hydroxide: side effects

      • constipation

      • systemic phosphate depletion (weakness, malaise, anorexia)

    •  Magnesium hydroxide: side effects

      • loose stools

      • ionic magnesium stimulates gastric release ("acid rebound")

      • magnesium trisilicate-- slow-acting antacid

    • Calcium carbonate (converted a calcium chloride in the stomach)

      • associated with "acid rebound"

      • with excessive, chronic use, calcium carbonate may cause:

        •  milk-alkali syndrome with elevation of:

          • serum calcium

          • phosphate

          • urea nitrogen

          • creatinine

          • bicarbonate levels

        • may result in renal calcinosis; possibly progressive renal insufficiency

    • Sodium bicarbonate: effective antacid, but systemic alkalosis may occur

  •  H₂ Receptor Antagonists

    • Effective inhibitor of stimulated and non-stimulated gastric acid secretion

    • Healing rates: similar between antacids and H₂ receptor antagonists (compliance better with receptor blockers)

    • Specific Agents:

      1. Cimetidine (Tagamet) -- reduces acid secretion responses to:histamine, caffeine, hypoglycemia, gastrin

         • few side effects; interaction with cytochrome P450 drug metabolizing system

         • tender gynecomastia: the two-week antiandrogenic effects (seen typically in Zollinger-Ellison disease patients following prolonged space ortreatment with large doses

      2. Ranitidine (Zantac)-- six times as potent as cimetadine in inhibiting gastric acid secretion

         • no antiandrogenic properties

         • smaller inhibitory effect on cytochrome P450 system then cimetidine (Tagamet)

      3.  Famotidine (Pepcid) and nizatidine (Axid): potent H₂ receptor blockers

         • rare blood dyscrasias and rare hepatotoxicity (similarto that seen with cimetadine and ranitidine)

  • Anticholinergic drugs:

    • atropine: not as effective as H₂ receptor blockers

      • Side effects:

        1. dryness of mouth

        2. blurred vision

        3. urinary retention

        4. cardiac arrhythmias

  • Coating Agents:

    • Sucralfate (Carafate)-complex polyaluminum hydroxide salt of sucrose sulfate

      • highly polar antacid pH: binds to ulcer bed (granulation tissue, not to gastric or duodenal mucosa)

        • decreases proton diffusion to the ulcer base

      • may increase endogenous tissue prostaglandins and may bind epidermal growth factors and other growth factors-- improving mucosal defense

    • Colloidal bismuth: -- bismuth-protein coagulant

      • may protect also from pepsin and acid digestion

      • may inhibit pepsin activity

      • prevents proton diffusion into the ulcer

      • Stimulates gastric mucosal secretion of protective agents:

      • Colloidal bismuth only class of antiulcer drugs that can eradicate H. pylori and cure associated gastritis

  • Prostaglandins:

    • reduction in basal and stimulated gastric acid secretion; enhanced mucosa resistance to injury (PGE₁/PGE₂).

  • Proton Pump Inhibitors:

    • Parietal cells H⁺ ion secretion depends on a H⁺,K⁺-ATPase pump-- promoting H K exchange

      • H⁺,K⁺-ATPase located in apical membraneto and tubulovesicular apparatus of parietal cells

      • Luminal surface of the membrane enzyme: exposed to gastric luminal acid

    • Omeprazole (Prilosec)and lansoprazole (Prevacid)inhibit the proton pump, effectively irreversibly -- requiring synthesis of new enzyme protein

    • Omeprazole and lansoprazole approved for treatment of:

      • duodenal ulcer

        •  may be used in conjunction with triple therapy

      • erosive esophagitis

      • gastric acid hypersecretory states, including Zollinger-Ellison syndrome

"Parietal Cell-HCl secretion"

courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

Friedman, L. S. and Peterson, W.L. Peptic Ulcer and Related Disorders In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 1597-1616.

• Important Drugs for Gastrointestinal Disorders

  • H₂ Histamine receptor blockers

    • cimetidine (Tagamet)

    • ranitidine (Zantac)

    • famotidine (Pepcid)

    • nizatidine (Axid)

  • Antimuscarinic drugs

    • Atropine

    • Propantheline

    • Pirenzepine

  • Proton pump inhibitor

    • omeprazole (Prilosec)

    • lansoprazole (Prevacid)

  • Mucosal protective agents

    • sucralfate (Carafate)

    • misoprostol (Cytotec)

  • Antidiarrheal drugs

    • Diphenoxylate

    • Kaopectate

    • Bismuth Subsalicylate

    • Loperamide

    • Paragoric

  • Laxative Drugs

    • Bisacodyl

    • Magnesium Hydroxide

    • Mineral Oil

    • Docusate

    • Lactulose

    • Methyl Cellulose

    • Psyllium

  • Antacids

    • Magnesium hydroxide

    • Aluminum hydroxide

    • Calcium carbonate

  • Drugs that dissolve gallstones

    • Chenodiol

    • Monoctanoin

  • Drugs acting on G.I. motility

    • Bethanechol

    • Metoclopramide