What is the mechanism of action of lactulose?

Mechanism of Action of Lactulose

Lactulose works primarily through bacterial fermentation in the colon, which acidifies the colonic contents, traps ammonia as ammonium ions, and creates an osmotic effect that increases bowel movements. 1

Primary Mechanisms

1. Bacterial Fermentation and Acidification

• Lactulose is a synthetic disaccharide (β-galactosido-fructose) that is not digested or absorbed in the small intestine 1
• When it reaches the colon intact, colonic bacteria metabolize lactulose, producing:
  • Short-chain fatty acids (SCFAs)
  • Acetic acid
  • Lactic acid 2
• This bacterial degradation causes acidification of the colonic contents 1

2. Ammonia Reduction (Important in Hepatic Encephalopathy)

• The acidification of colonic contents creates three important effects:
  • Converts ammonia (NH₃) to ammonium ions (NH₄⁺)
  • Traps the ammonium ions in the colon, preventing absorption
  • Creates a concentration gradient that draws ammonia from the blood into the colon 1
• This mechanism explains why lactulose is effective in hepatic encephalopathy, reducing blood ammonia levels 2

3. Osmotic Laxative Effect

• As a poorly absorbed disaccharide, lactulose creates an osmotic effect in the colon
• This osmotic action:
  • Draws water into the intestinal lumen
  • Increases stool water content
  • Softens stool consistency
  • Stimulates peristalsis 2
• The combined osmotic effect and laxative action expel the trapped ammonium ions from the colon 1

Secondary Mechanisms

1. Microbiome Modulation

• Lactulose promotes the growth of beneficial bacteria:
  • Increases Lactobacillus and Bifidobacteria counts 3
  • Reduces pathogenic bacteria including coliforms, Bacteroides, Salmonella, and Shigella 4
• These bacteria do not produce ammonia, further contributing to ammonia reduction 2

2. Bacterial Nitrogen Incorporation

• The bacterial fermentation process increases bacterial incorporation of nitrogen
• This increases bacterial mass and reduces the breakdown of nitrogen-containing compounds to ammonia 5

Clinical Applications Based on Mechanism

1. Hepatic Encephalopathy: Primary treatment due to its ammonia-reducing effects 2

   • Dosing: 30-45 mL (20-30g) every 1-2 hours until 2 bowel movements per day, then titrate to maintain 2-3 soft stools daily

2. Constipation: Effective as an osmotic laxative 2

   • Adult dosing: 10-20g (15-30 mL) daily, may increase to 40g daily if needed
   • Pediatric dosing (infants): 2.5-10 mL in divided doses 6

Common Side Effects and Limitations

• Gastrointestinal effects: Bloating, flatulence, abdominal cramping 2
• These side effects are dose-dependent and can limit clinical use
• Side effects are more pronounced at treatment initiation and often diminish over time

Clinical Pearls

• Lactulose requires bacterial metabolism to exert its therapeutic effects; antibiotics may reduce its efficacy
• The therapeutic effect in hepatic encephalopathy is not immediate and may take 24-48 hours
• For constipation, effects typically begin within 24-48 hours of administration
• In infants, careful monitoring for side effects is necessary, as bloating and flatulence can be particularly distressing 6
• Long-term use is generally safe but requires monitoring for electrolyte imbalances

Lactulose's multifaceted mechanism of action explains its versatility in treating conditions ranging from hepatic encephalopathy to constipation, with its primary effects stemming from bacterial fermentation in the colon.