Lactulose is used in preventing and treating clinical portal-systemic encephalopathy; first used in clinical practice in 1966. Its chief mechanism of action is by decreasing the intestinal production and absorption of ammonia. It has also gained popularity as a potential therapeutic agent for the management of subacute clinical encephalopathy. It is also a laxative for the treatment of chronic constipation and has undergone study as early as the 1960s. Its osmotic effect and its effect on intestinal motility receive credit for its therapeutic efficacy.
Lactulose can be useful for chronic constipation as a third-line agent, once lifestyle modifications and increasing fiber intake have failed. Because of its ability to significantly reduce intestinal transit time, it also possesses the ability to reduce hyper-saturation of deoxycholic acid, thereby inhibiting cholesterol stone formation. Recent studies have looked at lactulose for the development of novel anticancer therapeutic agents, due to its ability to bind to galectins (a carbohydrate binding protein that plays a role in tumor progression).
Lactulose, also known as 1,4 beta galactoside-fructose, is a non-absorbable synthetic disaccharide made up of galactose and fructose. The human small intestinal mucosa does not have the enzymes to split lactulose, and hence lactulose reaches the large bowel unchanged. Lactulose is metabolized in the colon by colonic bacteria to monosaccharides, and then to volatile fatty acids, hydrogen, and methane. Lactulose reduces intestinal ammonia production and absorption in three ways. First, the colonic metabolism of sugars causes a laxative effect via an increase in intraluminal gas formation and osmolality which leads to a reduction in transit time and intraluminal pH. This laxative effect is also beneficial for constipation. Next, lactulose promotes increased uptake of ammonia by colonic bacteria which utilize the trapped colonic ammonia as a nitrogen source for protein synthesis. The reduction of intestinal pH facilitates this process, which favors the conversion of ammonia (NH3) produced by the gut bacteria, to ammonium (NH4+), an ionized form of the molecule, unable to cross biological membranes. Finally, lactulose also causes a reduction in intestinal production of ammonia. The acidic pH destroys urease-producing bacteria involved in the production of ammonia. The unabsorbed disaccharide also inhibits intestinal glutaminase activity, which blocks the intestinal uptake of glutamine, and its metabolism to ammonia.
Although a variety of mechanisms of action of lactulose that limit the production and absorption of ammonia in the gut, as explained above, have been reported, it is probable that other laxatives could have the same effects with better tolerability. Lactulose originally received FDA approval in the USA in 1977, but there are concerns regarding the adequacy of data to support its efficacy. As lactulose has been believed to be the therapy for hepatic encephalopathy, it cannot be withheld from patients in need of the therapy from an ethical standpoint. Thus, it remains difficult to conduct human investigation review board approved placebo-controlled trials in the US to confirm or refute the efficacy of lactulose.
Although the oral route (as a syrup) has been the standard mode of administration for the past several decades, it is also effective as a rectal enema. Most of these studies were comparisons between lactulose/lactitol enemas and placebo. The few studies that have compared oral vs. rectal lactulose have demonstrated inconclusive findings in the long-term. Lactitol, a second generation disaccharide, is a crystalline powder but is not available in the United States. It is equally efficacious but better tolerated than lactulose and is usually prescribed at a dose of 10 to 90 g per day to cause two soft bowel movements per day.
At present, the most commonly used regimens of lactulose are as follows.
For constipation, administration of 15-45 ml (or 10-30 gm) 2-4 times daily, until the formation of soft stools.
In patients with hepatic encephalopathy, lactulose is typically given in syrup form at a dose of 15 to 30 mL two to four times a day to aim for two semisoft stools per day.
For acute hepatic encephalopathy, a common option is to administer a bolus of 45 ml (30 gm) and repeat it hourly until the first bowel movement. Once the episode of encephalopathy has subsided, the dose can be titrated to achieve 2-3 soft bowel movements on a daily basis.
This mode is preferred if there exists any risk of aspiration via the oral route. The preferred route is to administer it as 300ml in 700ml of water and have it retained in the colon for an hour, repeated every 2 hours until the episode resolves. The patient position should be in the lateral recumbent position to optimize intestinal distribution.
Because lactulose has insignificant absorption by the gut and undergoes rapid excretion by the kidneys, its effects remain localized to the gut microenvironment. Side-effects would include increased bowel sounds (borborygmi), increased flatus and a sensation of bloating. Since its intended use is to soften the stool quantity and increase the stool amount, its most significant side effect remains as diarrhea. The diarrhea is dose-dependent and decreases in severity with a reduction in the dose of lactulose.
The following are the contraindications of lactulose:
1) Patients with galactosemia: Lactulose, as a result of its chemical composition, contains galactose and is contraindicated in patients who require a galactose-free diet.
2) Diabetics: Although only a small fraction of lactulose undergoes systemic absorption, diabetes patients must use it with caution due to a potential to cause hyperglycemia in diabetic individuals as have been documented in a few studies.
3) Elderly population: Studies comparing the clinical efficacy and safety of other osmotic laxatives such as sorbitol against lactulose have concluded that in the elderly, lactulose causes increased nausea as a side effect. Sorbitol is thus a safer and an inexpensive drug to use in this population.
4) Pregnancy: Pregnancy is a stressor of hemodynamic physiology. Theoretically, via its osmotic action, the prolonged use of lactulose may lead to electrolyte imbalances.
From a pharmacokinetic standpoint, lactulose has negligible systemic absorption. However, like most laxatives, it has a propensity to bring about large changes in the body's fluid and electrolyte status. This activity would require periodic electrolyte monitoring, especially in the elderly and critically ill population. The effects are particularly profound regarding the sodium level, which commonly manifests as hypernatremia. In psychiatric patients on lithium therapy, there may be a risk for toxicity due to the decreased renal excretion of the drug as a result of volume depletion, which would require careful drug monitoring.
Clinically, documentation on lactulose toxicity is lacking. Specific studies using rats inoculated with various concentrations of lactulose syrup ranging from 0.5-5% revealed no evidence of toxicity. However, there have been studies indicating the ability of lactulose to induce lithium toxicity in psychiatric patients. This effect is more broadly attributable to lactulose's ability to induce dehydration through its osmotic action, depletion of total body volume and the resultant poor renal excretion of lithium. Although rare, documented allergic reactions to lactulose exist, typically in patients with milk allergy.
In the context of hepatic encephalopathy management, there are multiple decision-making steps involved to ensure the best form of patient care. These would range from the mode of administration of lactulose (either orally, rectally or via a nasogastric tube), the monitoring of the number of bowel movements to achieve the required frequency of 2-3 stools per day.
Communication between the physicians, pharmacists, and the nursing staff is of paramount importance to monitor frequent changes in mental status and accurately measure stool output. In certain situations, dose titration of the lactulose may also be required to prevent dehydration, diarrhea, and excoriation of the anal skin, requiring pharmaceutical intervention. Patients in the ICU who would require lactulose administered via an NG tube would need physical positioning designed to decrease the odds of aspiration.
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