Antidiarrheal agents Domina Petric, MD

Introduction Antidiarrheal agents may be used safely in patients with mild to moderate acute diarrhea. These agents should not be used in patients with bloody diarrhea, high fever or systemic toxicity. In these patients there is a risk of worsening the underlying condition. Antidiarrheal agents should be discontinued in patients whose diarrhea is worsening despite therapy. Antidiarrheals are also used to control chronic diarrhea caused by irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD).

Antidiarrheals Opioid agonists Colloidal bismuth compounds Bile salt-binding resins Octreotide

Opioid agonists Opioids have significant constipating effects. They increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses. Result is increased colonic transit time and fecal water absorption.

Opioid agonists These agents also decrease mass colonic movements and the gastrocolic reflex. Central nervous system effects and potential for addiction limit the usefulness of opioid agonists.

Opioid agonists Loperamide is a nonprescription opioid agonist that does not cross the blood-brain barrier. It has no analgesic properties or potential for addiction. Dose is 2 mg taken 1-4 times daily.

Opioid agonists Diphenoxylate is a prescription opioid agonist that has no analgesic properties in standard doses. Higher doses have CNS effecs. Prolonged use can lead to opioid dependance.

Opioid agonists Commercial preparations commonly contain small amounts of atropine to discourage overdosage: 2,5 mg diphenoxylate with 0,025 mg atropine. The anticholinergic properties of atropine may contribute to the antidiarrheal action.

Bile salt-binding resins Conjugated bile salts are normally absorbed in the terminal ileum. Diseases of the terminal ileum, like Crohn´s disease, or surgical resection lead to malabsorption of bile salts. Nonabsorbed bile salts may cause colonic secretory diarrhea.

Bile salt-binding resins The bile salt-binding resins are cholestyramine, colestipol and colesevelam. These agents may decrease diarrhea caused by excess fecal bile acids. Administration is per os three times daily before meals.

Bile salt-binding resins Adverse effects: bloating, flatulence, constipation and fecal impaction. In patients with diminished circulating bile acid pools these agents may lead to an exacerbation of fat malabsorption.

Bile salt-binding resins Cholestyramine and colestipol (but not colesevelam) bind a number of drugs and reduce their absorption. They should not be given within 2 hours of other drugs.

Somatostatin Somatostatin is a 14-amino-acid peptide that is released in the gastrointestinal tract and pancreas from paracrine cells, D cells and enteric nerves as well as from the hypothalamus.

Physiologic effects of somatostatin: Inhibits the secretion of numerous hormones and transmiters: gastrin, cholecystokinin glucagon, growth hormone insulin, secretin, 5-HT pancreatic polypeptide vasoactive intestinal peptide

Physiologic effects of somatostatin: It reduces intestinal fluid secretion and pancreatic secretion. It slows gastrointestinal motility and inhibits gallbladder contraction. It reduces portal and splanchnic blood flow. It inhibits secretion of some anterior pituitary hormones.

Octreotide The clinical usefulness of somatostatin is limited by its short half-life (3 minutes) when administered iv. Octreotide is a synthetic octapeptide with actions similar to somatostatin.

Octreotide When administered iv. serum half-life is 1,5 hours. In the case of subcutaneous injection, duration of action is 6-12 hours. A longer-acting formulation is available for once-monthly depot intramuscular injection.

Clinical uses of octreotide

Inhibition of endocrine tumor effects Gastrointestinal neuroendocrine tumors, carcinoid and VIPoma, cause secretory diarrhea and systemic symptoms: flushing and wheezing. In patients with nonresectable tumor, octreotide decreases secretory diarrhea and systemic symptoms.

Inhibition of endocrine tumor effects Ocreotide inhibits hormonal secretion. It may also slow tumor progression.

Other causes of diarrhea Octreotide inhibits intestinal secretion and has dose-related effects on bowel motility. In low doses of 50 mcg sc., it stimulates motility. At higher doses of 100-250 mcg sc., it inhibits motility.

Other causes of diarrhea Octreotide is effective in higher doses for the treatment of diarrhea due to: vagotomy dumping syndrome short bowel syndrome AIDS

Other causes of diarrhea Octreotide is useful in low doses for stimulation of small bowel motility in patients with small bowel bacterial overgrowth or intestinal pseudo-obstruction secondary to scleroderma.

Other uses Patients with pancreatic fistula-octreotide inhibits pancreatic secretion. Treatment of pituitary tumors-acromegaly. Gastrointestinal bleeding.

Adverse effects Impaired pancreatic secretion may cause steatorrhea, which can lead to fat-soluble vitamin deficiency. Alterations in gastrointestinal motility cause nausea, abdominal pain, flatulence and diarrhea.

Adverse effects Octreotide inhibits gallbladder contractility and alters fat absorption. Long-term use of octreotide can cause formation of sludge or gallstones in more than 50% of patients. This can lead rarely to acute cholecystitis.

Adverse effects Octreotide alters the balance among insulin, glucagon and growth hormone. Hyperglycemia or hypoglycemia (usually mild, less frequently) can occur. Other: hypothyroidism, bradycardia.

Literature Katzung, Masters, Trevor. Basic and clinical pharmacology.