Drugs Used in Gastrointestinal Disorders

Question 1

Helicobacter pylori

Answer 1

Is detectable in over 80% of patients with duodenal ulcers.

Question 2

Antacids

Answer 2

Antacids are weak bases that neutralize stomach acid by reacting with protons in the lumen of the gut and may also stimulate the protective functions of the gastric mucosa.

The antacids differ mainly in their absorption and effects on stool consistency.

Question 3

Popular antacids

Answer 3

• Magnesium Hydroxide: has a strong laxative effect.
• Aluminium Hydroxide: has constipating action.

Neither of these weak bases is significantly absorbed from the bowel.

• *Calcium carbonate and sodium bicarbonate are also weak bases, but they differ from aluminum and magnesium hydroxides in being absorbed from the gut. Because of their systemic effects, calcium and bicarbonate salts are less popular as antacids.

Question 4

H2 Receptor Antagonists

Answer 4

Cimetidine and other H2 antagonists (ranitidine, famotidine, and nizatidine) inhibit stomach acid production, especially at night. They are effective in the treatment of GERD, peptic ulcer disease, and nonulcer dyspepsia and in the prevention of stress-related gastritis in seriously ill patients. Although they are still used widely, their clinical use is being supplanted by the more effective and safe proton pump inhibitor.

Question 5

Proton pump inhibitors

Answer 5

Are lipophilic weak bases that diffuse into the parietal cell canaliculi, where they become protonated and concentrated more than 1000-fold. There they undergo conversion to compounds that irreversibly inactivate the parietal cell H*/K* ATPase, the transporter that is primarily responsible for producing stomach acid. Oral formulations of these drugs are enteric coated to prevent acid inactivation in the stomach. After absorption in the intestine, they are rapidly metabolized in the liver, with half-lives of 1-2 h. However, their durations of action are approximately 24 h, and they may require 3-4 d of treatment to achieve their full effectiveness.

Question 6

Proton pump inhibitors

Answer 6

Omeprazole Esomeprazole Lansoprazole Pantoptazole Rabeprazole

Question 7

Compare proton pump inhibitor to H2 antagonist.

Answer 7

Proton pump inhibitors are more effective than H2 antagonist for GERD and peptic ulcer and equally effective in the treatment of non-ulcer dyspepsia and prevention of stress related Mickelson bleeding. They’re also used for the treatment of Zollinger Ellison syndrome.

Question 8

Adverse effects of proton pump inhibitors.

Answer 8

Adverse effects of proton pump inhibitor occurs infrequently and includes diarrhea, abdominal pain and headache. Chronic treatment with proton pump inhibitor may result in hypergastrinemia. They do not increase the incidence of carcinoid or colon cancer. Proton pump inhibitors may decrease the order of bioavailability of vitamin B 12 in certain drugs that require acidity for the gastrointestinal absorption. Patient stake in proton pump in inhibitors have a small increase in the risk of respiratory and enteric infections.

Question 9

Sucralfate

Answer 9

An aluminum sucrose sulfate, sucralfate is a small, poorly soluble molecule that polymerizes in the acid environment of the stomach. The polymer binds to injured tissue and forms a protective coating over ulcer beds. Sucralfate accelerates the healing of peptic ulcers and reduces the recurrence rate. Unfortunately, sucralfate must be taken 4 times daily. Sucralfate is too insoluble to have significant systemic effects when taken by the oral route; toxicity is very low.

Question 10

Misoprostol

Answer 10

An analog of PGE1, misoprostol increases mucosal protection and inhibits acid secretion.

It is effective in reducing the risk of ulcers in users of nonsteroidal anti-inflammatory drugs (NSAIDs) but is not widely used because of the need for multiple daily dosing and poorly tolerated adverse effects (gastrointestinal upset and diarrhea).

Question 11

Colloidal bismuth

Answer 11

Bismuth has multiple actions, including formation of a protective coating on ulcerated tissue, stimulation of mucosal protective mechanisms, direct antimicrobial effects, and sequestration of enterotoxins.

Bismuth subsalicylate, a non-prescription formulation of bismuth and salicylate, reduces stool frequency and liquidity in infectious diarrhea.

Bismuth causes black stools.

Question 12

Antibiotics

Answer 12

Chronic infection with H pylori is present in most patients with recurrent non-NSAID-induced peptic ulcers. Eradication of this organism greatly reduces the rate of recurrence of ulcer in these patients. One regimen of choice consists of a proton pump inhibitor plus a course of clarithromycin and amoxicillin (or metronidazole in patients with penicillin allergy).

Question 13

. Drugs That Promote Upper Gastrointestinal Motility

Answer 13

• Prokinetic drugs that stimulate upper gastrointestinal motility are helpful for gastroparesis and for postsurgical gastric emptying delay.
• Their ability to increase lower esophageal sphincter pressures also makes them useful for some patients with GERD.
• In the past, cholinomimetic agonists such as bethanechol were used for GERD and gastroparesis, but the availability of less toxic agents has supplanted their use.
• The acetylcholinesterase inhibitor neostigmine is still used for the treatment of hospitalized patients with acute large bowel distention.
• In the enteric nervous system, dopamine inhibits cholinergic stimulation of smooth muscle contraction.
• Metoclopramide and domperidone are D2 dopamine receptor antagonists that promote gastrointestinal motility.
  
  • The D2 receptor-blocking action of these drugs in the area postrema is also of value in preventing emesis after surgical anesthesia and emesis induced by cancer chemotherapeutic drugs.
  • Side effects: When used chronically, metoclopramide can cause symptoms of parkinsonism, other extrapyramidal effects, and hyperprolactinemia. Because it does not cross the blood-brain barrier, domperidone is less likely to cause CNS toxicity.
• The macrolide antibiotic erythromycin promotes motility by stimulating motilin receptors. It may have benefit in some patients with gastroparesis.

Question 14

Laxatives

Answer 14

Laxatives increase the probability of a bowel movement by several mechanisms: an irritant or stimulant action on the bowel wall; a bulk-forming action on the stool that evokes reflex contraction of the bowel; a softening action on hard or impacted stool; and a lubricating action that eases passage of stool through the rectum.

Question 15

Antidiarrheal Agents

Answer 15

• The most effective antidiarrheal drugs are the opioids and derivatives of opioids that have been selected for maximal antidiarrheal and minimal CNS effect.
• Of the latter group, the most important are diphenoxylate and loperamide, meperidine analogs with very weak analgesic effects.
• Diphenoxylate is formulated with antimuscarinic alkaloids (eg, atropine) to reduce the likelihood of abuse.
• Loperamide is formulated alone.
• Kaolin, a naturally occurring hydrated magnesium aluminum silicate, is combined with pectin, an indigestible carbohydrate derived from apples in a popular nonprescription preparation that absorbs bacterial toxins and fluid, resulting in decreased stool liquidity. They can cause constipation and interfere with absorption of other drugs.
• Antidiarrheal agents may be used safely in patients with mild to moderate acute diarrhea. However, these agents should not be used in patients with bloody diarrhea, high fever, or systemic toxicity because of the risk of worsening the underlying condition.

Question 16

Drugs Used for Irritable Bowel Syndrome

Answer 16

• Irritable bowel syndrome (IBS) is associated with recurrent episodes of abdominal discomfort (pain, bloating, distention, or cramps) plus diarrhea or constipation (or both).
• The pharmacologic strategy is tailored to patients’ symptoms and includes antidiarrheal agents and laxatives, and for the treatment of abdominal pain, low doses of tricyclic antidepressants.
• The anticholinergic drugs dicyclomine and hyoscyamine are used as antispasmodics to relieve abdominal pain; however, their efficacy has not been convincingly demonstrated.
• Alosetron, a potent 5-HT3 antagonist, is approved for treatment of women with severe IBS with diarrhea. Alosetron can cause constipation, including rare complications of severe constipation that have required hospitalization or surgery, and rare cases of ischemic colitis. For this reason, its use is restricted.
• Lubiprostone, a laxative that activates the type 2 chloride channels in the small intestine, is approved for treatment of women with IBS with predominant constipation.
• Linaclotide has a similar therapeutic effect but acts more indirectly: It binds to and activates guanylyl cyclase-C on the luminal intestinal epithelial surface, resulting in increased intracellular and extracellular cGMP, which in turn leads to activation of the type 2 chloride channels.

Question 17

Drugs With Antiemetic Actions

Answer 17

• In addition to metoclopramide and other D2 dopamine receptor antagonists, useful antiemetics are drugs with H1 histamine blocking activity including diphenhydramine and several phenothiazines; antimuscarinic drugs such as scopolamine; the corticosteroid dexamethasone; and the cannabinoid receptor agonists dronabinol and nabilone.
• The 5-HT3 antagonists ondansetron, granisetron, dolasetron, and palonosetron are particularly useful in preventing nausea and vomiting after general anesthesia and in patients receiving cancer chemotherapy.
• Aprepitant, a newer antiemetic, is an antagonist of the neurokinin 1 (NK1) receptor, a receptor in the area postrema of the CNS that is activated by substance P and other tachykinins. Aprepitant is approved for use in combination with other antiemetics for prevention of the nausea and vomiting associated highly emetogenic chemotherapeutic regimens. Aprepitant can cause fatigue, dizziness, and diarrhea. As a substrate and an inhibitor of CYP3A4, aprepitant participates in many drug interactions.

Question 18

Drugs Used in Inflammatory Bowel Disease (IBD)

Answer 18

Question 19

Sites of 5-aminosalicylic acid (5-ASA) release from different formulations in the small and large intestines.

Answer 19

Question 20

Pancreatic Enzyme Replacements

Answer 20

Steatorrhea, a condition of decreased fat absorption together with an increase in stool fat excretion, results from inadequate pancreatic secretion of lipase. The abnormality of fat absorption can be significantly relieved by oral administration of pancreatic lipase (pancrelipase or pancreatin) obtained from pigs.

Pancraetic lipase is inactivated at a pH lower than 4.0; the enzyme should be taken as enteric-coated capsules unless the pH is raised with antacids or drugs that reduce acid secretion.

Question 21

Drugs That Inhibit the Formation of Gallstones

Answer 21

The formation of cholesterol gallstones can be inhibited by the bile acid derivative ursodiol, which decreases the cholesterol content of bile by decreasing hepatic cholesterol secretion and has other effects on hepatocyte canalicular membranes. Toxicity due to the drug is uncommon

Question 22

Sulfasalazine

Answer 22

Sulfasalazine (a combination of 5-ASA and sulfapyridine) has a higher incidence of adverse effects than the other 5-ASA drugs, due to the systemic absorption of the sulfapyridine moiety. These effects are dose related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, malaise, and severe hypersensitivity reactions. Other aminosalicylates, which do not contain sulfapyridine, are well tolerated.