Antidiarrheal Agents

Antidiarrheal agents include several drug classes, including opioid agonists, somatostatin analogues, adsorbents, and bile acid sequestrants. These medications mainly work through antimotility and/or antisecretory effects. Somatostatin analogues are particularly helpful for secretory diarrhea due to endocrine hormone-producing malignancies, while bile acid sequestrants can be used for conditions causing bile acid malabsorption diarrhea. Antidiarrheals can decrease the clearance of infectious pathogens and toxins and should be avoided in invasive infectious diarrhea.

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Overview

Diarrhea

Diarrhea is the passage of ≥ 3 loose or liquid stools within 24 hours.

Classification:

  • Based on duration:
    • Acute: ≤ 2 weeks 
    • Persistent: > 2 weeks but < 4 weeks
    • Chronic: ≥ 4 weeks
  • Based on etiology and pathophysiology:
    • Infectious diarrhea:
      • Inflammatory (invasion by an infectious organism)
      • Noninflammatory (no invasion of the mucosa by the organism)
    • Noninfectious diarrhea:
      • Secretory (efflux of electrolytes and water)
      • Osmotic (water drawn into the intestinal lumen)
      • Malabsorption (impaired nutrient absorption)
      • Inflammatory (inflammatory process causing mucosal damage)
      • Altered motility (rapid intestinal transit)

General management: 

  • Supportive care
  • Antimicrobials for specific infectious etiologies (not routinely required)
  • Antidiarrheal agents: 
    • Reduce the duration of diarrhea
    • Be aware that treatment can delay the extraction of pathogens and toxins.
    • Contraindications:
      • Diarrhea with fever
      • Bloody or mucoid stool
      • Diarrhea caused by Clostridioides difficile and Shigella
Workup for acute diarrhea antidiarrheal agents

Evaluation and management of patients with acute diarrhea:
Based on the history and physical exam, a determination can be made about whether the diarrhea is related to an infectious or noninfectious etiology (e.g., medications). Most patients will not require more than supportive care. However, those with indications for further workup may undergo laboratory and stool testing, which can help guide further therapy.

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Drug classes

  • Opioids 
  • Somatostatin analogues
  • Adsorbents
  • Bile acid sequestrants

Antidiarrheal properties

These drug classes may improve symptoms of diarrhea via:

  • ↓ GI motility (antimotility)
  • ↓ Secretion (antisecretory)

Opioid Agonists

Medications within this class

The opioid agonists utilized for their antidiarrheal activity are: 

  • Loperamide
  • Diphenoxylate

Mechanism of action

  • Opioid agonists act on mu receptors on nerves in the:
    • Myenteric plexus
    • Submucosal plexus 
  • Effects:
    • Inhibit peristalsis → ↑ colonic transit time → ↑ fecal water absorption
    • ↓ Epithelial fluid and electrolyte secretion 
    • ↓ Gastrocolic reflex
    • ↑ Anal tone → ↓ urgency and incontinence
  • Directly acts on: 
    • Smooth muscles of the intestine 
    • Secretory or absorptive epithelium 
  • Additionally, diphenoxylate is often combined with atropine (to prevent misuse) → may have an anticholinergic effect

Pharmacokinetics

Loperamide:

  • Absorption: poor oral absorption
  • Distribution: 
    • Poor CNS penetration
    • Protein binding: approximately 95% 
  • Metabolism: cytochrome P450 ((CYP) CYP2C8 and CYP3A4)
  • Excretion: feces

Diphenoxylate:

  • Absorption: well absorbed 
  • Distribution: 
    • CNS penetration (effects seen at higher doses)
    • Protein binding: approximately 80%
  • Metabolism:
    • Hepatic
    • Ester hydrolysis → diphenoxylic acid (active metabolite)
  • Excretion: 
    • Majority in feces 
    • Smaller quantities in urine

Indications

  • Loperamide:
    • Provides symptomatic relief in: 
      • Noninvasive diarrhea 
      • Mild traveler’s diarrhea 
      • Chronic diarrhea with inflammatory bowel disease (IBD)
    •  Off-label use:
      • Cancer treatment–induced diarrhea 
      • High enterocutaneous fistula or ileostomy output
  • Diphenoxylate: used in combination with atropine for acute diarrhea

Adverse effects

  • GI side effects:
    • Nausea
    • Abdominal cramps 
    • Constipation 
  • Allergic reactions
  • Torsades de pointes (in higher-than-recommended doses of loperamide)
  • CNS effects (in high doses of diphenoxylate)
    • Drowsiness/sedation
    • Euphoria
    • Confusion

Contraindications

These medications should be avoided in patients with:

  • Invasive diarrhea
    • Escherichia coli
    • Salmonella
    • Shigella
  • Pseudomembranous colitis

Drug interactions

  • Loperamide: QT-prolonging agents → QT prolongation and ventricular arrhythmias (e.g., torsades)
  • Diphenoxylate causes potential ↑ CNS depression when used with:
    • Alcohol
    • Cannabinoid products
    • Opioids
    • Barbiturates
    • Benzodiazepines
    • Antihistamines

Somatostatin Analogues

Mechanism of action

  • Octreotide mimics the effect of somatostatin.
  • Inhibits release of serotonin and other GI peptides and hormones: 
    • Gastrin 
    • Vasoactive intestinal peptide (VIP)
    • Cholecystokinin
    • Secretin
    • Motilin 
    • Insulin
    • Glucagon 
    • Growth hormone (GH)
  • Effects:
    • ↓ Intestinal fluid secretion
    • ↓ Pancreatic secretion
    • ↓ GI motility
    • ↓ Gallbladder contraction
    • ↓ Splanchnic and portal blood flow

Pharmacokinetics

  • Absorption: 
    • Available in oral, intramuscular, and subcutaneous forms 
    • Subcutaneous injections have rapid and complete absorption. 
    • Oral absorption decreases drastically when taken with food. 
  • Distribution: approximately 60% protein bound
  • Metabolism: hepatic 
  • Excretion: urine

Indications

  • Secretory diarrhea (and other symptoms) caused by: 
    • Carcinoid syndrome 
    • VIPoma 
    • Gastrinoma
  • Diarrhea due to other causes:
    • Vagotomy
    • Dumping syndrome
    • Short bowel syndrome
    • AIDS
    • Acute graft-versus-host (GvH) disease
    • Chemotherapy
  • Other uses:
    • Acromegaly 
    • Hepatorenal syndrome (HRS)
    • Bleeding esophageal varices (splanchnic vasoconstriction) 
    • Sulfonylurea-induced hypoglycemia

Adverse effects

  • GI: 
    • Nausea
    • Abdominal pain 
    • Gallstone formation (from ↓ gallbladder contractility)
    • Steatorrhea (from ↓ pancreatic secretion) → vitamin deficiencies
  • Endocrine: 
    • Hyperglycemia or hypoglycemia 
    • Hypothyroidism (suppresses thyroid-stimulating hormone secretion) 
  • Cardiac:
    • Bradycardia
    • Cardiac conduction disturbances 
    • Edema

Drug interactions

  • ↑ Risk of hypoglycemia
    • Androgens
    • Antidiabetic agents
    • Monoamine oxidase inhibitors (MAOIs)
    • Salicylates
    • Serotonin reuptake inhibitors
  • ↓ Serum octreotide concentrations:
    • Antacids
    • Antihistamines
    • Proton pump inhibitors (PPIs)
  • ↑ Serum octreotide concentrations: bromocriptine

Adsorbents

Medications in this class

  • Bismuth subsalicylate
  • Kaolin
  • Pectin

Mechanism of action

  • Adsorbents coat the GI tract → allows binding and elimination of:
    • Infectious pathogens
    • Toxins
  • Additional effect of bismuth subsalicylate: 
    • Antisecretory effect 
    • Anti-inflammatory

Indications

  • Acute diarrhea (including traveler’s diarrhea)
  • Dyspepsia 
  • Bismuth subsalicylate: used in quadruple therapy for H. pylori infection

Adverse effects

  • Diarrhea
  • Black tongue 
  • Black stools 
  • Ototoxicity
  • Reye syndrome in children

Contraindications

Bismuth subsalicylate should not be used for individuals with:

  • Allergy to salicylates
  • GI bleed

Bile Acid Sequestrants

Medications in this class

  • Cholestyramine
  • Colestipol
  • Colesevelam

Chemistry

  • Polymeric compounds
  • Work as ion-exchange resins (e.g., chloride is exchanged for bile acids)
Chemical structure of cholestyramine antidiarrheal agents

Chemical structure of cholestyramine

Image: “Cholestyramine” by Dahl J. License: CC0 1.0

Mechanism of action

  • Some conditions may cause malabsorption of bile salts (normally occurring in the terminal ileum) → secretory diarrhea
  • Bile acid sequestrants bind excess bile acids → form insoluble, nonabsorbable compounds → osmotically inactive 
  • Effect: ↓ secretion of water and electrolytes

Pharmacokinetics

  • Absorption: none
  • Excretion: feces

Indications

  • Bile acid malabsorption diarrhea (e.g., Crohn’s disease (CD), short bowel syndrome) 
  • Other:
    • Hypercholesterolemia
    • Pruritus from cholestasis

Adverse effects

  • Bloating
  • Flatulence
  • Constipation
  • Fat malabsorption → vitamin deficiencies

Drug interactions

Bile acid sequestrants can bind to many drugs, resulting in decreased absorption and therapeutic effect.

References

  1. Brunton, LL, et al. (2018). Goodman & Gilman’s the Pharmacological Basis of Therapeutics. Thirteenth edition, McGraw Hill Medical.
  2. Rang, HP, & Dale, MM. (2016). Rang and Dale’s Pharmacology. 8. ed, Elsevier, Churchill Livingstone.
  3. Trevor, AJ. (2015). Katzung & Trevor’s Pharmacology: Examination & Board Review. 11th edition, McGraw-Hill Medical, Lange.
  4. Barr, W, & Smith, A. Acute diarrhea in adults. American Family Physician, vol. 89, no. 3, Feb. 2014, pp. 180–89.
  5. Lexicomp Drug Information Sheets. (2021). UpToDate. Retrieved August 7, 2021, from:

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