LACTULOSE

Lactulose is a synthetic, non-digestible sugar used in the treatment of chronic constipation 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. It is produced commercially by isomerization of lactose.
It is broadly classified as an osmotic laxative.

IUPAC NAME  -   4-O-β-D-Galactopyranosyl-β-D-fructofuranose

Brands - Duphalac, loose


Dosage
Adult: PO Constipation Initial: 10-20 g (15-30 mL)/day. Max: 45 mL (or 40 g of the reconstituted oral formulation)/day. Hepatic encephalopathy 60-100 g (90-150 mL)/day in 3 divided doses; adjust accordingly. Rectal Hepatic encephalopathy Mix 200 g (300 mL w/ 700 mL water or 0.9% NaCl as a retention enema. Retain enema for 30-60 mins; repeat 4-6 hrly until oral medication can be administered.

Oral
Constipation
Adult: Initially, 10-20 g (15-30 ml) daily as a single dose or in 2 divided doses; gradually adjust according to patient's response. Max dose: 45 ml (or up to 40 g of the reconstituted oral powder formulation)/day.
Child: As 3.35 mg/5 ml solution: 1 mth to 1 yr: 2.5 ml; 1-5 yr: 5 ml; 5-10 yr: 10 ml; 10-18 yr: 15 ml. All doses to be given bid.
Oral
Hepatic encephalopathy
Adult: 60-100 g (90-150 ml) daily in 3 divided doses; adjust to produce 2 or 3 soft stools each day.
Rectal
Hepatic encephalopathy
Adult: Mix 200 g (300 ml) with 700 ml water or 0.9% sodium chloride as a retention enema. Retain enema for 30-60
minutes; repeat every 4-6 hr until oral medication can be administered.

Administration - May be taken with or without food. May be taken w/ meals to reduce GI discomfort. Dilute w/ water, milk, or fruit juice to improve taste.
Contraindications Galactosaemia, intestinal obstruction. Patients on low galactose diet.
Special Precautions Monitor electrolyte imbalance. Lactose intolerance; diabetics

Adverse Drug Reactions - Diarrhoea (dose-related), nausea, vomiting, hypokalaemia, bloating and abdominal cramps.

Potentially Fatal: Dehydration and hypernatraemia on aggressive treatment.
Drug Interactions May prevent release of mesalazine in the colon. Decreased effect with oral neomycin, antacids.


PREGNANCY :  Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Storage Oral: Store at 15-30°C (59-86°F). Rectal: Store at 2-30°C (36-86°F).

Mechanism of Action Lactulose promotes peristalsis by producing an osmotic effect in the colon with resultant distention. In hepatic encephalopathy, it reduces absorption of ammonium ions and toxic nitrogenous compounds, resulting in reduced blood ammonia concentrations.
Onset: 48 hr.

Absorption: Not appreciable (oral).

Metabolism: Via colonic flora to lactic acid and acetic acid.
Excretion: Faeces, urine (as unchanged drug).
CIMS Class Laxatives, Purgatives
ATC Classification A06AD11 - lactulose ; Belongs to the class of osmotically acting laxatives.


Constipation
Lactulose is used in the treatment of chronic constipation. It is safe for people of all ages, except that the dosage may have to be reduced for those in the very small part of the population that are afflicted with galactosemia because most commercially prepared lactulose also contains galactose. For adults, the dosage is that which causes an urgent daily bowel movement that cannot be ignored or resisted. A starting dosage of two tablespoons with breakfast is usually prescribed. But, the dosage can be increased as needed over time to up to three tablespoons with each meal.
Lactulose works by relieving constipation through a number of different methods. 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 over time, as required.
Lactulose is useful in treating people who enjoy abusing laxatives provided that they use lactulose as their only laxative drug, because it has very low toxicity yet produces powerful results.
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. For the same reason, it can be used to help children who develop functional constipation out of fear or embarrassment of using the toilet facilities at school. This is because, when dosed with lactulose at breakfast time, there won't be an alternative. Improved compliance can be obtained by masking the lactulose in food or drink at 25% of the prescribed dosage and increasing the dosage one teaspoon (5 ml.) every three days. The standard dosage is one teaspoon (5 ml) for each year of age up to age 16.
Lactulose is also commonly given to elderly people who have diminished mental or physical capacity to have a daily bowel movement. It is the treatment of choice for constipation in rest homes both because of its effectiveness and its lack of side effects.
Lactulose has an overly sweet taste that can be completely masked by mixing it with coffee, tea, fruit juice or desserts. Some commercial preparations come already pre-flavored. 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.
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 considered a prebiotic because it modulates the beneficial bacterial flora of the gut and is considered a digestive aid. Modulation of gut flora presumably works by reducing potential pathogenic bacteria such as Escherichia coli and Staphylococcal species in stool, with increase in non-urease producing Lactobacillus limiting ammonia production. Moreover, lactulose is converted to lactic and acetic acid which results in acidification of colonic contents. The low pH decreases passive non-ionic diffusion of ammonia thus lowering its systemic concentration. Furthermore, with its prebiotic potential, lactulose also encourages growth of probiotic bacteria such as Bifidobacterium species that are known to have health-promoting effects.
For stubborn cases of constipation, lactulose is sometimes combined with polyethylene glycol 3350Da, (sold as Miralax or Dulcolax Balance in the USA without prescription).
If lactulose is taken two or three times a day, especially with polytethylene glycol 3350DA, it can occasionally be explosive. If taken in the morning or at lunch on a regular basis, the action is generally complete by bedtime. However, the evening dosage can be problematic. 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 with plastic pants along with a chux pad for the bed is recommended. This is especially true if a sleeping pill is taken.
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, i.e. 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.


Hepatic encephalopathy

Lactulose is useful in treating the hyperammonemia caused by hepatic encephalopathy, because it helps "draw out" ammonia (NH3) from the body. It is useful for preventing hyperammonemia caused as a side effect of administration of valproic acid.
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).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.However, lactulose can effectively be used as secondary prophylaxis of hepatic encephalopathy in patients with cirrhosis. Moreover, recent studies showed improved cognitive functions of cirrhotic patients with minimal hepatic encephalopathy treated with lactulose.
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.
Lactulose for hepatic encephalopathy generally requires oral dosage of at least three tablespoons (45 ml) three or four times a day with episodic diarrhea and constant flatulence almost a certain side effect.