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Chapter: Basic & Clinical Pharmacology : Drugs Used in the Treatment of Gastrointestinal Diseases

Antidiarrheal Agents

Antidiarrheal agents may be used safely in patients with mild to moderate acute diarrhea.


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 tox-icity because of the risk of worsening the underlying condition. They should be discontinued in patients whose diarrhea is wors-ening despite therapy. Antidiarrheals are also used to control chronic diarrhea caused by such conditions as irritable bowel syn-drome (IBS) or inflammatory bowel disease (IBD).



As previously noted, opioids have significant constipating effects . They increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the sub-mucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption. They also decrease mass colonic movements and the gastrocolic reflex. Although all opi-oids have antidiarrheal effects, central nervous system effects and potential for addiction limit the usefulness of most.


Loperamide is a nonprescription opioid agonist that does notcross the blood-brain barrier and has no analgesic properties or potential for addiction. Tolerance to long-term use has not been reported. It is typically administered in doses of 2 mg taken one to four times daily. Diphenoxylate is a prescription opioid agonistthat has no analgesic properties in standard doses; however, higher doses have central nervous system effects, and prolonged use can lead to opioid dependence. Commercial preparations commonly contain small amounts of atropine to discourage overdosage (2.5 mg diphenoxylate with 0.025 mg atropine). The anticholinergic prop-erties of atropine may contribute to the antidiarrheal action.


See the section under Mucosal Protective Agents in earlier text.



Conjugated bile salts are normally absorbed in the terminal ileum. Disease of the terminal ileum (eg, Crohn’s disease) or surgical resection leads to malabsorption of bile salts, which may cause colonic secretory diarrhea. The bile salt-binding resins cho-lestyramine, colestipol, or colesevelam, may decrease diarrheacaused by excess fecal bile acids . These products come in a variety of powder and pill formulations that may be taken one to three times daily before meals. Adverse effects include bloating, flatulence, constipation, and fecal impaction. In patients with diminished circulating bile acid pools, further removal of bile acids may lead to an exacerbation of fat malabsorption. Cholestyramine and colestipol bind a number of drugs and reduce their absorption; hence, they should not be given within 2 hours of other drugs. Colesevelam does not appear to have significant effects on absorption of other drugs.



Somatostatin is a 14-amino-acid peptide that is released in thegastrointestinal tract and pancreas from paracrine cells, D cells, and enteric nerves as well as from the hypothalamus . Somatostatin is a key regulatory peptide that has many physiologic effects:


1. It inhibits the secretion of numerous hormones and transmit-ters, including gastrin, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, vasoactive intestinal peptide, and 5-HT.


2.  It reduces intestinal fluid secretion and pancreatic secretion.


3. It slows gastrointestinal motility and inhibits gallbladder con-traction.


4.  It reduces portal and splanchnic blood flow.


5.  It inhibits secretion of some anterior pituitary hormones.


The clinical usefulness of somatostatin is limited by its short half-life in the circulation (3 minutes) when it is administered by intravenous injection. Octreotide is a synthetic octapeptide with actions similar to somatostatin. When administered intravenously, it has a serum half-life of 1.5 hours. It also may be administered by subcutaneous injection, resulting in a 6- to 12-hour duration of action. A longer-acting formulation is available for once-monthly depot intramuscular injection.

Clinical Uses


A. Inhibition of Endocrine Tumor Effects


Two gastrointestinal neuroendocrine tumors (carcinoid, VIPoma) cause secretory diarrhea and systemic symptoms such as flushing and wheezing. For patients with advanced symptomatic tumors that cannot be completely removed by surgery, octreotide decreases secretory diarrhea and systemic symptoms through inhibition of hormonal secretion and may slow tumor progression.


B. Other Causes of Diarrhea


Octreotide inhibits intestinal secretion and has dose-related effects on bowel motility. In low doses (50 mcg subcutaneously), it stimu-lates motility, whereas at higher doses (eg, 100–250 mcg subcuta-neously), it inhibits motility. Octreotide is effective in higher doses for the treatment of diarrhea due to vagotomy or dumping syn-drome as well as for diarrhea caused by short bowel syndrome or AIDS. Octreotide has been used in low doses (50 mcg subcutane-ously) to stimulate small bowel motility in patients with small bowel bacterial overgrowth or intestinal pseudo-obstruction sec-ondary to scleroderma.


C. Other Uses


Because it inhibits pancreatic secretion, octreotide may be of value in patients with pancreatic fistula.. Octreotide is sometimes used in gastrointestinal bleeding .


Adverse Effects


Impaired pancreatic secretion may cause steatorrhea, which can lead to fat-soluble vitamin deficiency. Alterations in gastrointesti-nal motility cause nausea, abdominal pain, flatulence, and diar-rhea. Because of inhibition of gallbladder contractility and alterations in fat absorption, long-term use of octreotide can cause formation of sludge or gallstones in over 50% of patients, which rarely results in the development of acute cholecystitis. Because octreotide alters the balance among insulin, glucagon, and growth hormone, hyperglycemia or, less frequently, hypoglycemia (usually mild) can occur. Prolonged treatment with octreotide may result in hypothyroidism. Octreotide also can cause bradycardia.


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