Anesthesia Pharmacology Chapter 21:  Gastrointestinal Pharmacology

 

Gastrointestinal Issues:  Gastrokinetic Agents,  Antacids as preoperative medication and Antiemetic Agents.

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

• 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