Mechanism of Action of Lactulose
Lactulose is a synthetic disaccharide (β-galactosido-fructose) that is not digested or absorbed in the small intestine and exerts its therapeutic effects primarily through bacterial fermentation in the colon, resulting in acidification of colonic contents and osmotic effects. 1, 2
Primary Mechanisms
Lack of absorption: Lactulose is not hydrolyzed by human intestinal disaccharidases and passes undigested through the small intestine to reach the colon essentially unchanged 1, 3
Bacterial fermentation: In the colon, lactulose is metabolized by colonic bacteria to produce:
Osmotic effects: As a non-absorbed disaccharide, lactulose draws water into the intestinal lumen through osmosis, increasing stool water content and promoting peristalsis 2
Therapeutic Effects in Hepatic Encephalopathy
Lactulose is a primary treatment for hepatic encephalopathy with multiple mechanisms of action:
Trapping of ammonia: The acidification of colonic contents converts ammonia (NH₃) to ammonium ions (NH₄⁺), which cannot be absorbed across the colonic mucosa 1, 2
Reduced ammonia production: The acidic environment inhibits ammonia-producing bacteria while promoting growth of non-ammonia-producing bacteria like Lactobacillus 2, 6
Increased nitrogen excretion: Lactulose increases fecal bacterial mass, which incorporates nitrogen and is then excreted, removing potential neurotoxins from the body 6, 7
Altered bacterial metabolism: Lactulose shifts bacterial fermentation toward production of non-toxic acetate (increased from 65% to 89%) and away from potentially neurotoxic 3-6 carbon fatty acids (decreased from 35% to 11%) 7
Laxative effect: The osmotic effect flushes trapped ammonium ions from the colon, further reducing ammonia absorption 1, 2
Therapeutic Effects in Constipation
Osmotic laxative effect: Lactulose increases the amount of water in the large bowel by drawing fluid into the bowel or retaining administered fluid 2
Stimulation of peristalsis: The acidification of colonic contents promotes colonic peristalsis 2
Altered gut microbiota: Lactulose may increase beneficial bacteria like Bifidobacterium while reducing pathogenic species 4, 2
Dosing Considerations
For constipation: FDA-approved dose is 10-20g (15-30 mL or 1-2 packets) daily, which may be increased to 40g (60 mL or 2-4 packets) daily if needed 2
For hepatic encephalopathy: Initial treatment of overt hepatic encephalopathy requires 30-45 mL (20-30g) every 1-2 hours until the patient has at least 2 bowel movements per day, then titrated to maintain 2-3 soft stools daily 2
For severe hepatic encephalopathy: When oral administration isn't possible, an enema of 300 mL lactulose and 700 mL water can be administered 3-4 times daily, retained for at least 30 minutes 2
Potential Additional Mechanisms and Effects
Hydrogen production: Bacterial fermentation of lactulose produces hydrogen gas, which may have antioxidant properties that could reduce oxidative stress 5
Microbiome modulation: Lactulose may promote growth of beneficial bacteria while inhibiting pathogenic species 4, 3
Reduced endotoxin production: The altered colonic environment may reduce production and absorption of bacterial endotoxins 4