Medicine & USMLE

Diphenoxylate vs. Loperamide

Gastrointestinal Pharm
  1. H2 Blockers (Cimetidine, Ranitidine, Famotidine)
  2. Proton Pump Inhibitors (PPIs)
  3. Misoprostol
  4. Orlistat
  5. Antacids
  6. Bismuth & Sucralfate
  7. Octreotide
  8. Diphenoxylate vs. Loperamide
  9. Ondansetron
  10. Metoclopramide
  11. Bulk-forming Laxatives
  12. Senna
  13. Docusate
  14. Aprepitant


Diphenoxylate and loperamide are opioid drugs that are used in the treatment of diarrhea. They act at mu-opioid receptors in the GI tract or enteric nervous system to reduce gut motility. This action helps these drugs treat diarrhea, from causes such as irritable bowel syndrome and traveler’s diarrhea. Notably, loperamide cannot cross the blood brain barrier, so it has low abuse potential. In contrast, Diphenoxylate can cross the blood brain barrier, so it is usually combined with atropine to prevent drug abuse. Adverse effects of these drugs to look out for include constipation, nausea and dry mouth. Loperamide can also lead to QT elongation and increase the risk of torsades de pointes.

Key Points

  • Opioid Anti-diarrheals
    • Drug Names
      • Diphenoxylate 
      • Loperamide
    • Mechanism
      • µ-opioid receptor agonists → Slow gut motility
      • Loperamide does not cross BBB - low concern for addiction
      • Diphenoxylate does cross BBB - combine with atropine to prevent abuse
    • Clinical Use
      • Diarrhea
        • IBS, travelers diarrhea, etc.
      • Diphenoxylate is often combined with atropine to reduce risk of dependence
    • Adverse Effects
      • Loperamide:
        • Can have QT prolongation
        • Constipation
        • Nausea
        • Dry Mouth