How to manage diarrhea potentially caused by anticholinergic (anticholinergic) medication use?

Managing Diarrhea Potentially Caused by Anticholinergic Medications

Critical Safety Warning

Anticholinergic medications do not cause diarrhea—they actually increase the risk of severe complications and death when diarrhea is present from other causes. 1 The Infectious Diseases Society of America explicitly warns that routine use of medications with anticholinergic properties may lead to increased risk of severe outcomes, including death, from diarrhea caused by C. difficile and Clostridium perfringens 1. A case report documents fatal ischemic colitis in a patient receiving quetiapine and other anticholinergics, where decreased intestinal peristalsis progressed to colonic necrosis 2.

Understanding the Clinical Scenario

If a patient on anticholinergic medications develops diarrhea, the anticholinergic is not the cause—you must search for the actual etiology while recognizing that the anticholinergic may worsen outcomes. 1

Anticholinergics Reduce Bowel Motility, Not Increase It

• Anticholinergic agents decrease intestinal peristalsis and muscular tone of the intestinal wall, leading to constipation as their primary gastrointestinal effect 3, 4
• The National Comprehensive Cancer Network identifies anticholinergics (hyoscyamine, atropine, scopolamine, glycopyrrolate) as treatments for diarrhea in palliative care, not causes of it 1, 5
• Anticholinergics like cyproheptadine are specifically used to treat gastrointestinal symptoms including diarrhea in mast cell activation syndrome 1

When Anticholinergics Appear Related to Diarrhea

Paradoxical diarrhea from fecal impaction is the most likely scenario where anticholinergic use correlates with diarrhea 6:

• Anticholinergics cause severe constipation, which can progress to fecal impaction 2
• Liquid stool flows around the impaction, presenting as diarrhea 6
• This requires rectal examination to identify the impaction 6

Immediate Management Algorithm

Step 1: Assess Severity and Identify Red Flags

Determine if this is complicated diarrhea requiring hospitalization: 1

• Document fever, bloody stools, severe abdominal cramping, or signs of shock 7
• Assess for dehydration: orthostatic symptoms, weakness, dry mucous membranes, sunken eyes, altered mental status (≥4 indicators = severe dehydration) 7
• Check for abdominal distension, absent bowel sounds, or peritoneal signs suggesting bowel ischemia 2

Step 2: Rule Out Fecal Impaction

Perform digital rectal examination immediately 6:

• If impaction present: disimpaction, tap water enemas, increase laxatives (senna ± docusate 2-3 tablets BID-TID), consider polyethylene glycol or lactulose 1
• Reduce or discontinue the anticholinergic medication to prevent recurrence 1, 6

Step 3: Identify the True Cause of Diarrhea

Common etiologies in patients on anticholinergics: 6

• Infectious causes: C. difficile (especially if recent antibiotics), bacterial, viral, or parasitic pathogens 1, 6
• Medication-induced: chemotherapy (5-FU, irinotecan, capecitabine), antibiotics disrupting gut flora, radiation therapy 1, 6
• Mechanical obstruction: can present with alternating constipation and diarrhea 6

Obtain stool studies if: 1

• Fever, bloody stools, severe symptoms, or immunocompromised state present
• Recent antibiotic use (test for C. difficile toxin)
• Recent hospitalization or healthcare exposure

Step 4: Discontinue or Reduce Anticholinergic Burden

The anticholinergic medication is worsening the clinical situation, not causing the diarrhea: 1

• Immediately discontinue anticholinergic agents in patients with confirmed or suspected infectious diarrhea, particularly C. difficile or STEC infections 1
• Review all medications for anticholinergic burden: clozapine, olanzapine, and quetiapine have the highest central anticholinergic activity among antipsychotics 1
• If the anticholinergic cannot be stopped, reduce to the lowest effective dose 1

Step 5: Initiate Appropriate Treatment

For infectious diarrhea: 1

• C. difficile: metronidazole 500 mg PO/IV QID × 10-14 days or vancomycin 125-500 mg PO QID × 10-14 days 1
• Other bacterial pathogens: treat with appropriate antibiotics based on culture results 1
• Avoid loperamide and other antimotility agents in bloody diarrhea, suspected STEC, or C. difficile infection 1

For non-infectious diarrhea (after ruling out infection): 1, 8

• Loperamide 4 mg initially, then 2 mg after each unformed stool (maximum 16 mg/day) 1, 8
• Diphenoxylate/atropine 1-2 tablets every 6 hours PRN (maximum 8 tablets/day) if not already on opioids 1
• Bland/BRAT diet (bananas, rice, applesauce, toast) 1

For rehydration: 7

• Oral rehydration solution for mild-moderate dehydration 7
• IV isotonic fluids (lactated Ringer's or normal saline) for severe dehydration or inability to tolerate oral intake 7

Special Considerations

Chemotherapy-Induced Diarrhea

If the patient is receiving cancer treatment: 1

• Irinotecan causes acute cholinergic diarrhea (within hours) that responds to atropine 0.25-1 mg SC/IV 1
• Delayed diarrhea (>24 hours post-chemotherapy) requires loperamide and may be life-threatening 1
• Consider dose reduction or discontinuation of chemotherapy for grade 2-4 diarrhea 1

Elderly Patients

Exercise extreme caution with anticholinergics in older adults: 1

• Cognitive decline has been reported with H1 blockers having anticholinergic effects, especially worrisome in elderly populations 1
• Elderly patients are more susceptible to QT prolongation and cardiac effects 8
• Higher risk of urinary retention, confusion, and falls 5

Common Pitfalls to Avoid

• Never assume anticholinergics caused the diarrhea—they cause constipation, not diarrhea 3, 4
• Never continue anticholinergics in patients with infectious diarrhea, particularly C. difficile or toxin-mediated illness 1
• Never use antimotility agents (loperamide) in bloody diarrhea or suspected STEC infection—this increases risk of hemolytic uremic syndrome 1
• Never neglect rectal examination—missing fecal impaction leads to inappropriate treatment 6
• Never focus solely on antidiarrheal agents while neglecting fluid resuscitation—dehydration is the primary threat 7