Lactulose

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Lactulose
Lactulose structure.svg
Haworth projection of lactulose.svg
Haworth projection of lactulose (bottom)
Clinical data
Pronunciation /ˈlæktjᵿloʊz/
Trade names Cholac, Generlac, Consulose, Duphalac, others
AHFS/Drugs.com Monograph
MedlinePlus a682338
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration		 By mouth (oral solution)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Poorly absorbed
Metabolism 100% in colon by enteric bacteria
Onset of action 8 to 48 hours[1][2]
Biological half-life 1.7–2 hours
Excretion Fecal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.022.752
Chemical and physical data
Formula C12H22O11
Molar mass 342.296 g/mol
3D model (Jmol)
  (verify)

Lactulose is a non-absorbable sugar used in the treatment of constipation and hepatic encephalopathy.[3][4] It is used by mouth for constipation and either by mouth or in the rectum for hepatic encephalopathy.[3] It generally begins working after eight to twelve hours but may take up to two days to improve constipation.[1][2]

Common side effects include abdominal bloating and cramps. There is the potential for electrolyte problems to occur as a result of diarrhea it produces. No evidence of harm to the baby has been found when used during pregnancy.[3] It is generally regarded as safe during breastfeeding.[5] It is classified as an osmotic laxative.[6]

Lactulose was first made in 1929 and has been used medically since the 1950s.[7][8] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[9] It is available as a generic and brand-name product.[4] In various countries it could be purchased for about US$0.16 per 15 ml of syrup (10 g of lactulose) in 2015.[10][11] In the United States the cost of this amount is about US$0.63.[12] Lactulose is made from the milk sugar lactose, which is composed of two simple sugars, galactose and fructose.[13][3]

Medical uses[edit]

Constipation[edit]

Lactulose is used in the treatment of chronic constipation in patients of all ages as a long-term treatment.[14] Lactulose is used for chronic idiopathic constipation, i.e. chronic constipation occurring without any identifiable cause. 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 idiopathic constipation is adjusted depending on the constipation severity and desired effect, from a mild stool softener to causing diarrhea. Dosage is reduced in case of galactosemia as most preparations contain the monosaccharide galactose due to its synthesis process.

Hyperammonemia[edit]

Lactulose is useful in treating hyperammonemia (high blood ammonia), which can lead to hepatic encephalopathy. Lactulose helps trap the ammonia (NH3) in the colon and bind to it.[15] It does this by using gut flora to acidify the colon, transforming the freely diffusible ammonia into ammonium (NH+
4) which can no longer diffuse back into the blood.[16] It is also useful for preventing hyperammonemia caused as a side effect of administration of valproic acid.[17]

Lactulose for hepatic encephalopathy generally requires relatively large oral dosages 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.[18][19][20][21] 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.[21]

Special populations[edit]

No evidence of harm to the baby has been found when used during pregnancy.[3] It is generally regarded as safe during breastfeeding.[5]

Side effects[edit]

Common side effects of lactulose are abdominal cramping, borborygmus and flatulence. In normal individuals, overdose is considered uncomfortable, but not life-threatening.[22] 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 electrolyte disturbances such as low magnesium levels. Ingestion of lactulose does not cause a weight gain because it is nondigestible with no nutritional value. Although lactulose is less likely to cause dental caries than sucrose, as a sugar there is potential for this. This should be taken into consideration when taken by people with a high susceptibility to this condition.

Mechanism of action[edit]

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 of heat-processes:[23] the greater the heat, the greater amount of this substance (from 3.5 mg/L in low temperature pasteurized milk to 744 mg/L in in-container sterilized milk).[24] It is produced commercially by isomerization of lactose.

Lactulose is not absorbed in the small intestine nor broken down by human enzymes, 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 associated with flatulence.

Lactulose is metabolized in the colon by bacterial flora to short chain fatty acids including lactic acid and acetic acid. These partially dissociate, acidifying the colonic contents (increasing the H+ concentration in the gut).[16] This favors the formation of the nonabsorbable NH+
4 from NH3, trapping NH3 in the colon and effectively reducing plasma NH3 concentrations.

The effectiveness of lactulose in treating hepatic encephalopathy is somewhat controversial.[25][needs update][26] However, lactulose can effectively be used as secondary prophylaxis of hepatic encephalopathy in patients with cirrhosis.[27] Moreover, recent studies showed improved cognitive functions of cirrhotic patients with minimal hepatic encephalopathy treated with lactulose.[28]

Society and culture[edit]

Name[edit]

Lactulose is the international nonproprietary name(INN).[29] It is sold under various brand names.

Cost[edit]

It is available as a generic medication.[4] The wholesale price is about US$0.18 per 15 ml dose.[30] In the United States 30 doses of the liquid is about US$20.[12]

Availability[edit]

Lactulose is available without prescription in most countries, but a prescription is required in the United States and Austria.

Food additive[edit]

Lactulose is commonly used as a food additive to improve taste and promote intestinal transit time.

References[edit]

  1. ^ a b Goldman, edited by Ann; Hain, Richard; Liben, Stephen (2006). Oxford textbook of palliative care for children (2 ed.). Oxford: Oxford University Press. p. 352. ISBN 9780198526537. 
  2. ^ a b Helms, Richard A. (2006). Textbook of therapeutics : drug and disease management (8 ed.). Philadelphia, Pa. [u.a.]: Lippincott Williams & Wilkins. p. 1310. ISBN 9780781757348. 
  3. ^ a b c d e "Lactulose". The American Society of Health-System Pharmacists. Retrieved Aug 11, 2015. 
  4. ^ a b c Hamilton, Richard J. (2013). Tarascon pocket pharmacopoeia : 2013 classic shirt-pocket edition (27 ed.). Burlington, Ma.: Jones & Bartlett Learning. p. 111. ISBN 9781449665869. 
  5. ^ a b Jones, Wendy (2013). Breastfeeding and Medication. Routledge. p. 127. ISBN 9781136178153. 
  6. ^ Whitlow, Charles (2009). Improved Outcomes in Colon and Rectal Surgery. New York: Informa Healthcare. p. 366. ISBN 9781420071535. 
  7. ^ McSweeney, P.L.H.; Fox, P.F. (2009). Advanced dairy chemistry. (3rd ed.). New York: Springer-Verlag. p. 236. ISBN 9780387848655. 
  8. ^ Schumann, C (November 2002). "Medical, nutritional and technological properties of lactulose. An update.". European journal of nutrition. 41 Suppl 1: I17–25. PMID 12420112. doi:10.1007/s00394-002-1103-6. 
  9. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016. 
  10. ^ "Lactulose". mshpriceguide.org. Retrieved 26 March 2017. 
  11. ^ "Lactulose Solution 500ml". Weldricks Pharmacy (UK). Retrieved 31 March 2017.  A UK source of lactulose at £2.95 for 500ml ($0.11/15ml).
  12. ^ a b "Lactulose Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 25 March 2017.  Source gives cost for 473 ml as about $20.
  13. ^ Kuntz, Hans-Dieter (2008). Hepatology textbook and atlas : history, morphology, biochemistry, diagnostics, clinic, therapy (3 ed.). Heidelberg: Springer. p. 887. ISBN 9783540768395. 
  14. ^ "Lactulose". nih.gov. Retrieved 25 August 2015. 
  15. ^ 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. PMID 21251030. doi:10.1111/j.1365-2036.2010.04574.x. 
  16. ^ 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. PMC 1432706 Freely accessible. PMID 3570029. doi:10.1136/gut.28.3.255. 
  17. ^ Gerstner, Thorsten; Buesing, Deike; Longin, Elke; Bendl, Claudia; Wenzel, Dieter; Scheid, Brigitte; Goetze, Gisela; Macke, Alfons; Lippert, Gerhard; Klostermann, Wolfgang; Mayer, Geert; Augspach-Hofmann, Regine; Fitzek, Sabine; Haensch, Carl-Albrecht; Reuland, Markus; Koenig, Stephan A. (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. 15 (6): 443–448. ISSN 1059-1311. PMID 16787750. doi:10.1016/j.seizure.2006.05.007. 
  18. ^ 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. PMID 18371132. doi:10.1111/j.1572-0241.2008.01798.x. 
  19. ^ 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. PMID 19392860. doi:10.1111/j.1365-2036.2009.04018.x. 
  20. ^ 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. PMID 18482250. doi:10.1111/j.1365-2982.2008.01142.x. 
  21. ^ 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. PMID 21112950. doi:10.1136/gut.2009.205476. 
  22. ^ "Safety Data Sheet Lactulose" (PDF). 2015. Retrieved 3 December 2016. 
  23. ^ M. Luzzana; D. Agnellini; P. Cremonesi; G. Caramenti; S. De Vita (September–October 2003). "Milk lactose and lactulose determination by the differential pH technique" (PDF). Le Lait. 83 (5): 409–16. doi:10.1051/lait:2003022. 
  24. ^ 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" (PDF). Food Chemistry. 84: 447–50. doi:10.1016/S0308-8146(03)00268-1. 
  25. ^ Als-Nielsen B, Gluud LL, Gluud C (2004). Als-Nielsen, Bodil, ed. "Nonabsorbable disaccharides for hepatic encephalopathy". Cochrane Database Syst Rev (2): CD003044. PMID 15106187. doi:10.1002/14651858.CD003044.pub2. 
  26. ^ Shawcross DL, Jalan R (July 2004). "Treatment of hepatic encephalopathy: it's not lactulose". BMJ. 329 (7457): 112; author reply 112. PMC 449830 Freely accessible. PMID 15242927. doi:10.1136/bmj.329.7457.112. 
  27. ^ 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. PMID 19501587. doi:10.1053/j.gastro.2009.05.056. 
  28. ^ 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. PMID 17326150. doi:10.1002/hep.21533. 
  29. ^ "International Nonproprietary Names for Pharmaceutical Preparations. Recommended International Non-Proprietary Names (Rec. I.N.N.): List 7" (PDF). World Health Organization. 1967. p. 8. Retrieved 9 November 2016. 
  30. ^ "Lactulose". International Drug Price Indicator Guide. Retrieved 11 August 2015. 

External links[edit]

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