Lactulose

Lactulose

Systematic (IUPAC) name
4-O-β-D-Galactopyranosyl-β-D-fructofuranose OR (2S,3R,4S,5R,6R)-2-((2R,3S,4S,5R)-4,5-dihydroxy-2,5-bis(hydroxymethyl) tetrahydrofuran-3-yloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
Clinical data
Trade names	Constulose
AHFS/Drugs.com	monograph
MedlinePlus	a682338
Pregnancy cat.	B(US)
Legal status	P (UK)
Routes	Oral
Pharmacokinetic data
Bioavailability	Poorly absorbed
Metabolism	100% in colon by enteric bacteria
Half-life	1.7-2 hours
Excretion	Fecal
Identifiers
CAS number	4618-18-2 Y
ATC code	A06AD11
PubChem	CID 11333
DrugBank	APRD01063
ChemSpider	10856 Y
UNII	9U7D5QH5AE Y
KEGG	D00352 Y
ChEBI	CHEBI:6359 Y
ChEMBL	CHEMBL296306 Y
Chemical data
Formula	C12H22O11
Mol. mass	342.296 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C12H22O11/c13-1-4-6(16)7(17)8(18)11(21-4)22-9-5(2-14)23-12(20,3-15)10(9)19/h4-11,13-20H,1-3H2/t4-,5-,6+,7+,8-,9-,10+,11+,12-/m1/s1 Y Key:JCQLYHFGKNRPGE-FCVZTGTOSA-N Y
N(what is this?)  (verify)

Lactulose (/ˈlæktjʉloʊz/) is a synthetic, non-digestible sugar used in the treatment of chronic constipation^[1] and hepatic encephalopathy, a complication of liver disease. It is a disaccharide (double-sugar) formed from one molecule each of the simple sugars (monosaccharides) fructose and galactose. The commercial syrup used for treatment of constipation is dyed yellow-orange. It is produced commercially by isomerization of lactose.

Constipation

Lactulose is used in the treatment of chronic constipation,^[2]. The metabolites of lactulose draw water into the bowel, causing a cathartic effect through osmotic action. It is safe for people of all ages, except for those in a very small percentage of the population that are galactose intolerant. Dosage may have to be adjusted over time to produce the desired effect because the laxative effect can decline with daily treatment.

Lactulose works by increasing the water content and volume of the stools in the bowel, making them softer and easier to pass. Lactulose is made up of sugar molecules and is partly broken down by the bacteria that live in the lower part of the gut. This leads to the contents of the gut becoming more acidic because there are carboxylic acids among its metabolites, which are not absorbed from the lower bowel. That in turn causes water to be retained in the lower bowel. This increases the amount of water in the stools, softening them and making them easier to pass. The added volume of gas and flatulence caused by fermentation of the lactulose adds to the volume of the fecal material, and makes it easier to expel. The slightly acidic condition of the colon caused by the presence of acids causes active peristalsis. The combined effect of all of these processes relieves constipation in a very effective manner.

Lactulose is useful in treating people with chronic constipation due to forgetting or ignoring the need for defecation. The treatment is to start the dosage at a low amount and then gradually increase it over a period of weeks until the urgency is such that a daily bowel movement cannot possibly be ignored. After an efficacious dosage is determined, it is maintained indefinitely or increased as needed over time.

Lactulose is useful in treating people who abuse laxatives provided that they use lactulose as their only laxative drug, because it has very low toxicity yet produces powerful results.

Lactulose is useful for negating the constipating effects of opiates and opioids, as in individuals who are on narcotic pain medication, are opioid dependent, or are receiving Opioid Replacement Therapy such as with methadone or buprenorphine for a previous opioid dependency.

Lactulose is useful for treatment of hemorrhoids because it produces a soft bowel movement without any straining.

Lactulose is helpful for treating children who withhold their bowel movements out of fear because when taken in sufficient quantity and then withheld, it produces a very insistent, irresistible and powerful urge to defecate.^[3]

Lactulose is considered a prebiotic because it modulates the beneficial bacterial flora of the gut and is considered a digestive aid.^[4]

Lactulose has an overly sweet taste that can be completely masked by mixing it with fruit juice or desserts. It can take 24 to 48 hours to work, but generally produces results within 4 hours if taken on a daily basis. It is best taken at breakfast along with a bowl of bran cereal.

For stubborn cases of constipation, lactulose is sometimes combined with polyethylene glycol 3350Da, (sold as Miralax or Dulcolax Balance in the USA without prescription).

Some authorities recommend lactulose twice a day. However, an evening dosage can be problematic. When taken on a regular basis, it tends to work in about four hours. If given to small children who are in diapers, this is not a problem. However, for older children and adults, there is the ever present danger of voluminous defecation during sleep or being awake for hours on the toilet with a feeling of imminent expulsion. A juvenile or adult diaper is recommended along with protective plastic pants. This is especially true if a sleeping pill is taken.^{[citation needed]}

In common with other osmotic laxatives, lactulose can cause electrolytic imbalances in sensitive individuals (see side effects below). However, it tends to do this less because it does not rely on mineral salts to draw fluid into the intestinal tract and also because it relies on nonosmotic modes of action: It stimulates peristalsis through acidification and gas and increases feeling of urgency through enlarging the volume of the bowel contents.

Lactulose is sold over the counter (without prescription) in most countries in the world. In the United States and Austria, it requires a prescription over unfounded fears that it could be dangerous to diabetics. However, it is an indigestible sugar and has been proved to be safe even for them. ^[5]

Hepatic encephalopathy

In treating hepatic encephalopathy, lactulose helps "draw out" ammonia (NH₃) from the body.^[6]

Lactulose is metabolized in the colon by bacterial flora to short chain fatty acids including the production of the lactic acid and acetic acid. This partially dissociates, acidifying the colonic contents (increasing the H⁺ concentration in the gut).^[7] This favors the formation of the nonabsorbable NH₄⁺ from NH₃, trapping NH₃ in the colon and effectively reducing plasma NH₃ concentrations.

The effectiveness of lactulose in treating hepatic encephalopathy is somewhat controversial.^[8][9]

Lactulose, also an osmotic laxative, is not absorbed, does not affect the absorption of spironolactone and may be used by diabetics. It is used in patients with cirrhosis/hepatic encephalopathy to limit the proliferation of ammonia forming gut organisms and increase the clearance of protein load in the gut.

Lactulose for hepatic encephalopathy generally requires oral dosage three or four times a day with diarrhea and constant flatulence almost a certain side effect.

Lactulose Breath Test

Lactulose is used as a test of small intestine bacterial overgrowth syndrome (SIBO). Recently the reliability of it for diagnosing SIBO has been seriously questioned.^{[10][11][12][13]} A large amount of it is given with subsequent testing of molecular hydrogen gas in the breath. The test is positive if an increase in exhaled hydrogen occurs before that which would be expected by normal colonocyte digestion. An earlier result has been hypothesized to indicate digestion occurring within the small intestine. An alternate explanation for differences in results is the variance in small bowel transit time among tested subjects.^[13]

Side effects

Common side effects of lactulose are abdominal cramping, borborygmus, gas and pungent flatulence that some people find difficult to control in social situations. Excessively high dosage can cause explosive and uncontrollable diarrhea. In normal individuals, overdose is considered uncomfortable, but not life threatening. Uncommon normal side effects are nausea and vomiting.

In sensitive individuals, such as the elderly or people with reduced kidney function, excess lactulose dosage can result in dehydration and electrolytic disturbances such as high sodium levels.

Although lactulose has less potential to cause dental caries than sucrose, there is a minimal potential because it is a sugar. This should be taken into consideration when taken by people with a high susceptibility to this condition. ^[14]

References

1. ^ Voskuijl W, de Lorijn F, Verwijs W, et al. (November 2004). "PEG 3350 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial". Gut 53 (11): 1590–4. doi:10.1136/gut.2004.043620. PMC 1774276. PMID 15479678. http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=15479678. 
2. ^ Lactulose, MedlinePlus Drug Information
3. ^ Lactulose at The Medical Dictionary
4. ^ Shukla, S.; Shukla, A.; Mehboob, S.; Guha, S. (2011). "Meta-analysis: The effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy". Alimentary Pharmacology & Therapeutics 33 (6): 662. doi:10.1111/j.1365-2036.2010.04574.x. 
5. ^ The Annals of Pharmacotherapy: Vol. 26, No. 10, pp. 1277–1282.
6. ^ Paik YH, Lee KS, Han KH, et al. (June 2005). "Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study". Yonsei medical journal 46 (3): 399–407. doi:10.3349/ymj.2005.46.3.399. PMC 2815818. PMID 15988813. http://www.eymj.org/abstracts/viewArticle.asp?year=2005&page=399. ^{[dead link]}
7. ^ Patil DH, Westaby D, Mahida YR, et al. (March 1987). "Comparative modes of action of lactitol and lactulose in the treatment of hepatic encephalopathy". Gut 28 (3): 255–9. doi:10.1136/gut.28.3.255. PMC 1432706. PMID 3570029. http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=3570029. 
8. ^ Als-Nielsen B, Gluud LL, Gluud C (2004). "Nonabsorbable disaccharides for hepatic encephalopathy". Cochrane Database Syst Rev (2): CD003044. doi:10.1002/14651858.CD003044.pub2. PMID 15106187. 
9. ^ Shawcross DL, Jalan R (July 2004). "Treatment of hepatic encephalopathy: it's not lactulose". BMJ (Clinical research ed.) 329 (7457): 112; author reply 112. doi:10.1136/bmj.329.7457.112. PMC 449830. PMID 15242927. http://bmj.com/cgi/pmidlookup?view=long&pmid=15242927. 
10. ^ Vanner, S (2008). "The lactulose breath test for diagnosing SIBO in IBS patients: another nail in the coffin.". The American Journal of Gastroenterology 103 (4): 964–965. doi:10.1111/j.1572-0241.2008.01798.x. PMID 18371132. http://www3.interscience.wiley.com/journal/119387435/abstract?CRETRY=1&SRETRY=0. 
11. ^ Barrett, J. S., Irving, P. M., Shepaerd, S. J., Muir, J. G., & Gibson, P. R. (2009). "Comparison of the prevalence of fructose and lactose malabsorption across chronic intestinal disorders.". Alimentary Pharmacology & Therapeutics 20 (2): 165–174. doi:10.1111/j.1365-2036.2009.04018.x. PMID 19392860. http://www3.interscience.wiley.com/journal/122325605/abstract. 
12. ^ Grover, M., Kanazawa, M., Palsson, O., Chitkara, D., Gangarosa, L., Drossman, D., et al. (2008). "Small intestinal bacterial overgrowth in irritable bowel syndrome: association with colon motility, bowel symptoms, and psychological distress.". Neurogastroenterology Motility 20 (9): 998–1008. doi:10.1111/j.1365-2982.2008.01142.x. PMID 18482250. http://www3.interscience.wiley.com/journal/120124642/abstract. 
13. ^ ^{a b} Yu D, Cheeseman F, Vanner S. (2011). "Combined oro-caecal scintigraphy and lactulose hydrogen breath testing demonstrate that breath testing detects oro-caecal transit, not small intestinal bacterial overgrowth in patients with IBS.". Gut 60 (3): 334-340. doi:10.1136/gut.2009.205476. PMID 21112950. http://gut.bmj.com/content/early/2010/11/26/gut.2009.205476.abstract. 
14. ^ Moynihan, P. J.; Ferrier, S.; Blomley, S.; Wright, W. G.; Russell, R. R. B. (1998). "Acid production from lactulose by dental plaque bacteria". Letters in Applied Microbiology 27 (3): 173–177. doi:10.1046/j.1472-765X.1998.00403.x. PMID 9750322. 

External links

• Medline Plus