A 72-year-old man comes to the office due to watery diarrhea and abdominal cramps. The symptoms began several days after he started chemotherapy for metastatic colon cancer. He denies hematochezia, melena, or bulky, foul-smelling stools. Vital signs are within normal limits, and physical examination is unremarkable. Laboratory testing reveals no electrolyte abnormalities and no leukocytosis. Stool testing is negative for infection and fecal occult blood. The patient is advised to take a medication after each loose stool. The medication works by inhibiting the release of acetylcholine in the intestinal wall but does not cross the blood-brain barrier. Which of the following is the most likely medication prescribed for this patient?
Antidiarrheal agents | |
Opioid agonists (eg, loperamide, diphenoxylate with atropine, tincture of opium) |
|
Bulk forming agents (eg, psyllium, pectin) |
|
Bismuth subsalicylate |
|
Octreotide |
|
Bile acid sequestrants (eg, cholestyramine) |
|
GI = gastrointestinal. | |
This patient with uncomplicated, chemotherapy-induced diarrhea was prescribed loperamide. Loperamide is an opioid agonist that exerts its antidiarrheal effects by binding to mu opiate receptors in the colonic myenteric plexus. This inhibits acetylcholine release from myenteric plexus neurons, decreasing activity of the intestinal smooth muscles and slowing peristalsis. Transit time within the intestine is prolonged, allowing for increased water absorption. In addition, the anticholinergic effects also result in decreased secretion from the intestinal epithelia, further reducing stool volume and increasing fecal consistency.
Unlike other opiates (eg, hydrocodone, fentanyl), loperamide undergoes high first-pass metabolism and does not cross the blood-brain barrier, allowing it to be used without opiate-related adverse events (eg, respiratory depression, sedation) or threat of abuse. The only side effect is constipation, which can be avoided with careful dose titration. Diphenoxylate, another opiate used for diarrhea, is less extensively metabolized and crosses the blood-brain barrier. To discourage abuse, diphenoxylate is typically combined with a small amount of atropine, an anticholinergic medication that results in dry mouth, flushing, pupil dilation, and urinary retention when used in large amounts.
(Choice A) Aprepitant is a neurokinin-1 receptor antagonist used for chemotherapy-related nausea and vomiting, not diarrhea.
(Choice B) Bismuth subsalicylate is frequently used for diarrhea and dyspepsia. Although its mechanism of action is not clearly understood, it stimulates the intestinal absorption of fluid (reducing diarrhea) and inhibits prostaglandin synthesis (reducing hypermotility). It does not inhibit acetylcholine release.
(Choice C) Fentanyl is an opiate commonly used as an analgesic and sedative. Although it causes constipation, it crosses the blood-brain barrier and therefore is not used for diarrhea due to the risk of systemic opiate-related adverse events (eg, respiratory depression, abuse).
(Choice E) Neostigmine is an acetylcholinesterase inhibitor that increases acetylcholine within the synapse. Its cholinergic effects would worsen this patient's diarrhea.
(Choice F) Octreotide is a somatostatin analogue that is sometimes used for refractory chemotherapy-induced diarrhea; however, it exerts its antidiarrheal effect by reducing secretion of pancreatic and gastrointestinal hormones (eg, secretin, gastrin, vasoactive intestinal peptide).
Educational objective:
Loperamide is an opioid agonist that exerts its antidiarrheal effects by binding to mu opiate receptors in the colonic myenteric plexus, which inhibits acetylcholine release, decreases intestinal smooth muscle activity, and slows peristalsis. It undergoes high first-pass metabolism and does not cross the blood-brain barrier, thus avoiding systemic opiate-related adverse events (eg, sedation, respiratory depression).