Drugs Often Overlooked as a Cause of Chronic Diarrhea

Table 1 – Types of DID¹

Type		Mechanism		Common Examples
Osmotic Diarrhea		• Drugs draws water and ions into intestinal lumen		Artificial sweeteners, alpha glucosidase inhibitors, Mg laxative, polyethylene glycol, ACE inhibitors
Secretory Diarrhea		• Drug causes imbalance between absorption and secretion in intestinal lumen • Characteristics: large volumes of stool, lack of red or white blood cells in stool, absence of other symptoms		Caffeine, carbamazepine, chemotherapeutic agents (epirubicin, docetaxel, flucytosine), colchicine, laxatives, metformin, NSAIDs, simvastatin, cholinesterase inhibitors
Motility Diarrhea		• Drug increases or decreases migratory motor complex activity to disrupt intestinal motility; occurs by either:  o Hypermotility/decreased transit time  o Hypomotility/stasis causing bacterial overgrowth		Acetylcholine esterase inhibitors, irinotecan, erythromycin, thyroid hormones, colchicine
Inflammatory Diarrhea		• Drug disrupts epithelium in gastrointestinal tract		Antibiotics (clindamycin, amoxicillin, ampicillin, cephalosporins), chemotherapeutic agents (5-fluorouracil, methotrexate, irinotecan, cisplatin, doxorubicin), etanercept, NSAIDs, olmesartan, oral contraceptives, PPIs, SSRIs, laxatives

Abbreviations: ACE (angiotensin converting enzyme); NSAID (nonsteroidal anti-inflammatory drug); PPI (proton pump inhibitor); SSRI (selective serotonin reuptake inhibitor)

Table 2 – Medication Classes Associated With DID¹

Therapeutic Category		Mechanism		Comments
Laxatives		• Osmotic: magnesium salts, polyethylene glycol • Secretory: stimulant laxatives • Inflammatory		• Can be caused by use or abuse • Causes 10-20 bowel movements per day • Identifying triggering medication  o Stool laxative screens for diphenolic laxatives and polyethylene glycol-containing laxatives  o Stool osmotic gap calculation   o <75 mOsm/kg: senna, bisacodyl, sodium-containing laxatives   o >75 mOsm/kg: laxatives containing magnesium, sorbitol, lactulose, polyethylene glycol   o Negative osmotic gap: phosphate or sulfate-containing laxative
NSAIDs		• Secretory • Inflammatory		• Occurs in 3-9% of NSAIDs users • Nonspecific colitis is most common occurrence of NSAID damage
Cardiovascular Medications		• Osmotic: ACE inhibitors, propranolol, quinidine, hydralazine, procainamide • Secretory: antiarrhythmic (quinidine, digoxin), ticlopidine • Motility: ticlopidine • Inflammatory: olmesartan, ticlopidine		• DID is rare in patients on beta-blockers and ACE inhibitors • Olmesartan – cases of sprue-like enteropathy have been reported • Ticlopidine – may cause microscopic colitis
Antidiabetic Medications		• Osmotic: alpha glucosidase inhibitors (acarbose, miglitol) • Secretory: metformin		• Diarrhea common among diabetic patients; often wrongly attributed to autonomic imbalance • Metformin: dose-dependent diarrhea common; malabsorptive diarrhea can occur after a stable, long-term dose • Exenatide, orlistat – can cause steatorrhea
Antineoplastic Agents		• Secretory: idarubicin, epirubicin, pentostatin, mitoguazone, docetaxel, flucytosine • Motility: irinotecan • Inflammatory: 5-fluorouracil, methotrexate, irinotecan, cisplatin, doxorubicin, ipilimumab, rituximab, mercaptopurine, tyrosine kinase inhibitors		• Diarrhea common in patients taking 5-fluorouracil, capecitabine, and irinotecan • Bortezomib, erlotinib, gefitinib, sorafenib, sunitinib, imatinib: cause diarrhea in 30-50% of patients • Ipilimumab: causes diarrhea in most patients; can cause severe colitis leading to colon perforation • Irinotecan: causes diarrhea in 87% of patients  o Early onset (within 24 hours): associated with cholinergic symptoms; treat with atropine or an antihistamine  o Late onset: unpredictable and dose-dependent; associated with intestinal villous atrophy, crypt hypoplasia, and crypt dilation; use dose modification to treat
Immunosuppresive Agents		• Inflammatory: Mycophenolate mofetil (MMF)		• Development of infective damage can occur in patients taking MMF  o 60% of patients on MMF who experience diarrhea have concurrent infective damage  o 40% of patients taking MMF who experience diarrhea develop erosive enterocolitis  o To improve symptoms: administer divided doses, reduce dose, or discontinue drug
Psychotropic Medications		• Inflammatory: SSRIs (paroxetine, sertraline)		• Lithium – associated with increased risk of GI effects
GI Medications				• PPIs – associated with collagenous and lymphocytic colitis • H2 blockers – possible association with lymphocytic colitis • Possible increased risk of Crohn’s disease in patients taking PPIs and H2 blockers concurrently

Abbreviations: ACE (angiotensin converting enzyme); GI (gastrointestinal); NSAID (nonsteroidal anti-inflammatory drug); PPI (proton pump inhibitor); SSRI (selective serotonin reuptake inhibitor)