Lactulose

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Lactulose
Lactulose structure.svg
Lactulose ball-and-stick.png
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.
Legal status
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 YesY
ATC code A06AD11
PubChem CID 11333
DrugBank DB00581
ChemSpider 10856 YesY
UNII 9U7D5QH5AE YesY
KEGG D00352 YesY
ChEBI CHEBI:6359 YesY
ChEMBL CHEMBL296306 YesY
Chemical data
Formula C12H22O11 
Mol. mass 342.296 g/mol
 YesY (what is this?)  (verify)

Lactulose /ˈlæktlz/ 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. Lactulose is not normally present in raw milk, but is a product due to the heat-processes:[2] the more the heat, the more the presence of this substance (from 3.5 mg/l in low temperature pasteurized milk to 744 mg/l in in-container sterilized milk).[3] It is produced commercially by isomerization of lactose.

It is broadly classified as an osmotic laxative. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[4]

Medical uses[edit]

Constipation[edit]

Lactulose is used in the treatment of chronic constipation.[5] in patients of all ages as a long-term treatment.

Lactulose is used for chronic idiopathic constipation, i.e. chronic constipation occurring without any identifiable cause. This is by far the most common finding.

Lactulose may be used to counter the constipating effects of opioids, and in the symptomatic treatment of hemorrhoids as a stool softener.

The dosage of lactulose for chronic ideopathic constipation is adjusted depending on the constipation severity and desired effect, from a mild stool softener to a strong, irresistible bowel movement. Dosage is reduced in case of galactosemia as most preparation contain the monosaccharide galactose due to its synthesis process.

Hyperammonemia[edit]

Lactulose is useful in treating hyperammonemia (high blood ammonia). This can be caused by hepatic encephalopathy. Lactulose helps trap the ammonia (NH3) in the colon.[6] It does this by using gut flora to acidify the colon, transforming the freely diffusible ammonia into ammonium (NH4+) which can no longer diffuse back into the blood.[7] It is also useful for preventing hyperammonemia caused as a side effect of administration of valproic acid.[8]

Lactulose for hepatic encephalopathy generally requires relatively large oral dosage three or four times a day with episodic diarrhea and constant flatulence almost a certain side effect. People who take lactulose at this level of dosage generally end up wearing an adult diaper and plastic pants for any activities away from home or at night (with a chux pad for the bed) because the diarrhea can occur swiftly and without much warning.

Small intestine bacterial overgrowth[edit]

Lactulose is used as a test of small intestine bacterial overgrowth (SIBO). Recently the reliability of it for diagnosing SIBO has been seriously questioned.[9][10][11][12] 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.[12]

Availability[edit]

Lactulose is available without prescription in most countries. However, a prescription is required in the United States and Austria mainly over unfounded fears that it could be harmful to diabetics. Even though it is approved in most countries as a food additive, it is not allowed in the United States because it is viewed there as a pharmaceutical drug.

Side effects[edit]

Food Additive[edit]

Lactulose is commonly used as a food additive to improve taste, promote intestinal health and promote intestinal transit time. Lactulose is known for its good acceptance, with limited side effects, similar to many other food products.

Laxative[edit]

At higher dosage, in pharmaceutical usage, common side effects of lactulose are abdominal cramping, borborygmus, meteorism and pungent, noisy flatulence that some people find difficult to control in social situations. In normal individuals, overdose is considered uncomfortable, but not life-threatening.[13] Uncommon 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.

Ingestion of lactulose does not cause a weight gain because it is a nondigestible, low calorie sugar that contains only about one calorie per millitre.

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.

Mechanism of action[edit]

Lactulose is a disaccharide that is not absorbed in the intestine nor broken down by human enzymes, and thus stays in the digestive bolus through most of its course, causing retention of water through osmosis leading to softer, easier to pass stool. It has a secondary laxative effect in the colon, where it is fermented by the gut flora, producing metabolites which have osmotic powers and peristalsis-stimulating effects (such as acetate), but also methane involved in flatulence.

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.[14][15] However, lactulose can effectively be used as secondary prophylaxis of hepatic encephalopathy in patients with cirrhosis.[16] Moreover, recent studies showed improved cognitive functions of cirrhotic patients with minimal hepatic encephalopathy treated with lactulose.[17]

Lactulose 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.

References[edit]

  1. ^ Voskuijl W, de Lorijn F, Verwijs W, Hogeman P, Heijmans J, Mäkel W, Taminiau J, Benninga M (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. 
  2. ^ M. Luzzana, D. Agnellini, P. Cremonesi, G. Caramenti, S. De Vita (September–October 2003). "Milk lactose and lactulose determination by the differential pH technique". Le Lait 83 (5): 409–16. doi:10.1051/lait:2003022. 
  3. ^ E. Marconi, M. C. Messia, A. Amine, D. Moscone, F. Vernazza, F. Stocchi, G. Palleschi (2004). "Heat-treated milk differentiation by a sensitive lactulose assay". Food Chemistry 84: 447–50. doi:10.1016/S0308-8146(03)00268-1. 
  4. ^ "WHO Model List of EsentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  5. ^ Lactulose, MedlinePlus Drug Information
  6. ^ Shukla, S; Shukla, A; Mehboob, S; Guha, S (Mar 2011). "Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy.". Alimentary pharmacology & therapeutics 33 (6): 662–71. doi:10.1111/j.1365-2036.2010.04574.x. PMID 21251030. 
  7. ^ a b Patil DH, Westaby D, Mahida YR, Palmer KR, Rees R, Clark ML, Dawson AM, Silk DB (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. 
  8. ^ Gerstner, T; Buesing, D; Longin, E; Bendl, C; Wenzel, D; Scheid, B; Goetze, G; Macke, A; Lippert, G; Klostermann, W; Mayer, G; Augspach-Hofmann, R; Fitzek, S; Haensch, CA; Reuland, M; Koenig, SA (Sep 2006). "Valproic acid induced encephalopathy--19 new cases in Germany from 1994 to 2003--a side effect associated to VPA-therapy not only in young children.". Seizure : the journal of the British Epilepsy Association 15 (6): 443–8. doi:10.1016/j.seizure.2006.05.007. PMID 16787750. 
  9. ^ Vanner S (April 2008). "The lactulose breath test for diagnosing SIBO in IBS patients: another nail in the coffin". Am. J. Gastroenterol. 103 (4): 964–5. doi:10.1111/j.1572-0241.2008.01798.x. PMID 18371132. 
  10. ^ Barrett JS, Irving PM, Shepherd SJ, Muir JG, Gibson PR (July 2009). "Comparison of the prevalence of fructose and lactose malabsorption across chronic intestinal disorders". Aliment. Pharmacol. Ther. 30 (2): 165–74. doi:10.1111/j.1365-2036.2009.04018.x. PMID 19392860. 
  11. ^ Grover M, Kanazawa M, Palsson OS, Chitkara DK, Gangarosa LM, Drossman DA, Whitehead WE (September 2008). "Small intestinal bacterial overgrowth in irritable bowel syndrome: association with colon motility, bowel symptoms, and psychological distress". Neurogastroenterol. Motil. 20 (9): 998–1008. doi:10.1111/j.1365-2982.2008.01142.x. PMID 18482250. 
  12. ^ a b Yu D, Cheeseman F, Vanner S (March 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): 334–40. doi:10.1136/gut.2009.205476. PMID 21112950. 
  13. ^ http://www.usp.org/pdf/EN/referenceStandards/msds/1356803.pdf
  14. ^ Als-Nielsen B, Gluud LL, Gluud C (2004). "Nonabsorbable disaccharides for hepatic encephalopathy". In Als-Nielsen, Bodil. Cochrane Database Syst Rev (2): CD003044. doi:10.1002/14651858.CD003044.pub2. PMID 15106187. 
  15. ^ Shawcross DL, Jalan R (July 2004). "Treatment of hepatic encephalopathy: it's not lactulose". BMJ 329 (7457): 112; author reply 112. doi:10.1136/bmj.329.7457.112. PMC 449830. PMID 15242927. 
  16. ^ Sharma BC, Sharma P, Agrawal A, Sarin SK (September 2009). "Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo". Gastroenterology 137 (3): 885–91, 891.e1. doi:10.1053/j.gastro.2009.05.056. PMID 19501587. 
  17. ^ Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R (March 2007). "Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy". Hepatology 45 (3): 549–59. doi:10.1002/hep.21533. PMID 17326150. 

External links[edit]