Mechanism of Action of Lactulose
Lactulose works as an osmotic laxative by drawing water into the intestine to hydrate and soften stool, and in hepatic encephalopathy, it acidifies colonic contents through bacterial fermentation, trapping ammonia as the ammonium ion and preventing its absorption. 1, 2
Primary Mechanisms
For Constipation (Osmotic Effect)
- Lactulose is a synthetic disaccharide that is not absorbed or metabolized in the small intestine, reaching the colon essentially unchanged 2, 3
- Once in the colon, it draws water into the intestinal lumen, creating an osmotic gradient that hydrates and softens stool 1
- This osmotic effect promotes peristalsis and accelerates colonic transit, particularly through the ascending colon, with transit time decreasing from approximately 13 hours to 7 hours 4
- The accelerated transit is associated with mass movements in the colon, which are the primary mechanism for moving contents distally 4
For Hepatic Encephalopathy (Ammonia-Lowering Effect)
- Colonic bacteria ferment lactulose into short-chain fatty acids (primarily acetic and lactic acid), which acidify the colonic contents 2, 3
- This acidification (lower pH) converts ammonia (NH₃) to the ammonium ion (NH₄⁺), which is charged and cannot cross the colonic membrane back into the bloodstream 2
- The pH gradient between acidic colonic contents and blood causes ammonia to migrate from blood into the colon, where it becomes trapped as ammonium 2
- The laxative effect then expels the trapped ammonium from the body before it can be reabsorbed 2
Secondary Mechanisms
Bacterial Flora Modulation
- Bacterial fermentation of lactulose increases bacterial nitrogen incorporation and overall bacterial mass, reducing the breakdown of other nitrogen compounds to ammonia 5
- Lactulose creates intestinal conditions favorable to Lactobacillus acidophilus while inhibiting pathogenic bacteria including coliforms, bacteroides, Salmonella, and Shigella 3, 6
- The acidic environment and presence of carbohydrate substrate reduce bacterial production of potential cerebral toxins beyond just ammonia 5
Additional Effects
- Lactulose may function as an indirect antioxidant by promoting bacterial hydrogen production during fermentation, which has been proposed to reduce oxidative stress 7
- Urinary excretion of absorbed lactulose is minimal (3% or less), confirming that its effects are primarily local in the colon rather than systemic 2
Clinical Implications
Common Pitfalls
- Gastrointestinal side effects (bloating, flatulence, abdominal cramps) occur in approximately 20% of patients due to the fermentation process producing gas 8, 9
- Starting at lower doses (10-20 g daily) and titrating upward minimizes these dose-dependent side effects 8, 9
- Excessive dosing can lead to diarrhea with complications including hypokalemia and hypernatremia from fluid and electrolyte losses 9