Lactulose

Overview

Lactulose (Cephulac®, Kristalose®) is a nonabsorbable disaccharide used in dogs and cats as an ammonia detoxicant and osmotic laxative. It is primarily administered to reduce blood ammonia concentrations in patients with hepatic encephalopathy and is also used for the management of constipation.

Lactulose is metabolized by colonic bacteria into organic acids, increasing osmotic pressure within the colon, drawing water into the bowel, and acidifying the colonic contents. This promotes laxation while converting ammonia (NH3) into ammonium (NH4+), which is retained in the colon and eliminated in the feces.

Mechanism of Action (MOA): Lactulose is a nonhydrolyzable galactose–fructose disaccharide that reaches the colon unchanged, where bacterial metabolism produces lactic, formic, and acetic acids, as well as carbon dioxide. These acids increase colonic osmotic pressure, enhance water retention in the bowel, acidify the colonic contents, and facilitate the trapping and fecal elimination of ammonia as ammonium ions, drawing ammonia from the blood into the colon and lowering mucosal and bacterial urease activity, which further reduces ammonia generation. Lactulose can also be considered a prebiotic; it increases colonic lactobacilli and bifidobacteria, and reversible changes in fecal microflora have been shown in healthy dogs.

Indications

Lactulose is used in dogs and cats primarily to reduce blood ammonia concentrations in patients with hepatic encephalopathy and as an osmotic laxative for the management of constipation.

• Hepatic encephalopathy: Adjunctive treatment for the prevention and management of hepatic encephalopathy (portosystemic encephalopathy) by reducing blood ammonia concentrations; lactulose is used in acute and chronic hepatic encephalopathy, including in dogs with congenital portosystemic shunts. It improves clinical signs but does not treat the underlying disease.
• Constipation: Used as an osmotic laxative for the management of constipation, including megacolon; as a stool softener in rectal or anal prolapse and in rectoanal polyps, and in perineal hernia as part of conservative management or before surgery; and to ease defecation in colorectal strictures or masses.
• Bowel preparation before surgery: Given by mouth or by high enema instillation before surgery for extrahepatic bile duct obstruction, to alter the enteric flora and reduce enteric translocation of opportunistic pathogens.

Dosage (Reference)

Dog

In dogs, lactulose is administered orally for hepatic encephalopathy and constipation. For acute hepatic encephalopathy, it may also be administered as a retention enema; rectal dosing is used in acute hepatic failure when oral dosing is hazardous, enemas are used for megacolon, and lactulose is given by mouth or by high enema before surgery for extrahepatic bile duct obstruction. Dosage should be adjusted according to clinical response and stool consistency.

Cat

In cats, lactulose is used orally for hepatic encephalopathy and constipation. A retention enema may be used for acute hepatic encephalopathy or acute, severe constipation; rectal dosing is used in acute hepatic failure when oral dosing is hazardous, enemas are used for constipation, obstipation or megacolon, and lactulose is given by mouth or by high enema before surgery for extrahepatic bile duct obstruction. Liquid and crystal formulations are available.

Warnings & Precautions

Lactulose should be used cautiously in dogs and cats with conditions that may increase the risk of fluid, electrolyte, or metabolic disturbances. Its therapeutic effects depend on normal colonic bacterial metabolism.

• Intestinal obstruction: Contraindicated in patients with gastrointestinal obstruction or at risk of perforation.
• Diabetes mellitus: Use cautiously because lactulose syrup contains free lactose and galactose, which may alter insulin requirements; per 10 g of lactulose, the solution contains less than 1.6 g galactose, less than 1.2 g lactose and up to 1.2 g of other sugars, and the crystals less than 0.3 g of galactose and lactose together.
• Fluid and electrolyte imbalance: Use cautiously in patients with pre-existing fluid or electrolyte disturbances, as diarrhea may exacerbate these abnormalities.
• Gut dysbiosis: Patients with gut dysbiosis, including potentially antibiotic-induced dysbiosis, may have a reduced response because lactulose requires bacterial metabolism for its activity.
• Long-term therapy: Serum electrolytes should be monitored periodically in patients with pre-existing fluid or electrolyte disorders or during prolonged treatment (months).
• Diabetic monitoring: Monitor glucose control during the initial stages of treatment in diabetic patients; disruption of glycemic control is primarily theoretical.
• Hepatic encephalopathy monitoring: Adjust the dose to maintain 2–3 soft stools daily and monitor serum ammonia concentrations and the patient’s hepatic status when used for hepatic encephalopathy; dehydration and hypokalemia, which excessive doses can cause, are among the conditions that provoke hepatic encephalopathy.
• Post-enema monitoring: After retention enema administration, measure the pH of the enema effluent and repeat the procedure if the pH is greater than 6.
• Severe encephalopathy: Do not give lactulose by mouth to severely encephalopathic animals at risk of aspiration; it may be given as a retention enema instead.
• Electrocautery: In people, a theoretical hazard may exist during electrocautery at proctoscopy or colonoscopy; hydrogen gas that accumulates in significant concentration may cause an explosive reaction in the presence of an electrical spark (not reported with lactulose), so a thorough bowel cleansing with a non-fermentable solution is advised first.
• Pregnancy and lactation: Lactulose does not impair fertility in laboratory animals and has no known teratogenic or mutagenic effects; whether it passes into milk is unknown, but it would be unexpected.
• After perineal hernia repair: Avoid stool softeners postoperatively, as they may lead to diarrhea and fecal soiling in the first days after surgery, especially after a bilateral repair.
• Constipation monitoring: Monitor defecation frequency and stool consistency at least twice a week initially, then weekly or biweekly as the patient responds.
• Laxative overuse and enema technique: Overuse of laxatives and enemas can cause diarrhea, and improper enema technique can damage the colonic mucosa.

Drug Interactions

The clinical effects of lactulose depend on bacterial metabolism within the colon and its ability to acidify colonic contents. Drugs that alter intestinal bacteria, gastrointestinal pH, bowel motility, or fluid and electrolyte balance may reduce its efficacy or increase the risk of adverse effects, and lactulose may in turn alter the absorption or effect of some other drugs; these interactions have been reported, or are theoretical, in humans or animals; unless otherwise noted, use together is not necessarily contraindicated, but the potential risks should be weighed and additional monitoring performed when appropriate.

• Oral antacids (eg, aluminum-, calcium-, or magnesium-containing products): May reduce colonic acidification and decrease the efficacy of lactulose.
• Antidiarrheal agents (eg, kaolin/pectin, loperamide): May counteract the laxative effect and reduce the ammonia-lowering effect of lactulose.
• Oral anti-infective agents (eg, amoxicillin, cephalexin, clindamycin, tylosin): May reduce lactulose efficacy by eliminating the intestinal bacteria responsible for its metabolism; in hepatic encephalopathy, if this happens (the stool fails to acidify, testable with litmus paper, and the laxative effect is lost), the antimicrobial should be discontinued unless it is specifically targeting an infection.
• Diuretics (eg, furosemide): May have additive effects on serum electrolyte disturbances.
• Glutamine: May antagonize the ammonia-lowering effects of lactulose.
• Other laxatives (eg, polyethylene glycol 3350, psyllium): Concurrent use is not recommended because loose stools may be falsely attributed to lactulose, resulting in inadequate therapy for hepatic encephalopathy; other laxatives may also have additive effects on GI motility and increase the risk of adverse effects.
• Neomycin: May theoretically reduce lactulose efficacy by eliminating intestinal bacteria; however, some data suggest a synergistic effect when both drugs are used for hepatic encephalopathy.
• Warfarin: Lactulose may increase the anticoagulant response of warfarin; enhanced monitoring is required if the two are used together.
• Drugs released in the colon pH-dependently (eg, 5-aminosalicylic acid): As the lactulose dose increases, colonic pH falls, and such drugs can be inactivated.

Side Effects & Overdose

Side Effects

Lactulose is generally well tolerated in dogs and cats. Adverse effects are primarily gastrointestinal, occurring particularly early in treatment or with excessive doses.

• Gastrointestinal effects: Flatulence, gastric distention, and abdominal cramping may occur early in therapy and generally diminish with continued treatment.
• Diarrhea: Excessive dosing may result in diarrhea and indicates that the dose should be reduced.
• Fluid and electrolyte disturbances: Diarrhea from excessive doses may lead to dehydration, hypokalemia, and hypernatremia.
• Palatability (cats): Cats dislike the taste of lactulose syrup, and administration may be difficult; some dogs also dislike the taste. Lactulose crystals mixed with food may be better accepted, and lactulose may be mixed in food or other liquids to improve palatability, provided the whole dose is consumed.
• Hyperlactatemia: Lactulose is one of the drugs associated with type B2 hyperlactatemia.
• Calcium (dogs): In one study of 17 dogs with portosystemic shunts treated with lactulose for more than 3 weeks, no hypercalcemia was identified, although the change in ionized calcium correlated positively with the lactulose dose, possibly a dose-dependent association.
• Nausea and vomiting: Reported in people.

Overdose

Lactulose overdose primarily results in excessive gastrointestinal effects and secondary fluid and electrolyte losses.

• Clinical signs: Flatulence, diarrhea (which can be severe, liquid and projectile), abdominal cramping (which can be painful, from gas generation), and dehydration.
• Management: Replace fluids and electrolytes as needed and reduce the lactulose dose; for a suspected overdose, consult a 24-hour veterinary poison consultation center.
• Acute toxicity (rodents): The acute oral LD50 is 48.8 mL/kg in mice and greater than 30 mL/kg in rats.

Key Notes

Practical clinical points that help optimize the effective use of lactulose in dogs and cats in everyday veterinary practice:

• Adjunctive therapy: Lactulose improves the clinical signs of hepatic encephalopathy but does not correct the underlying liver disease.
• Prebiotic effect: In addition to its osmotic laxative action, lactulose can also be considered a prebiotic, as it forms free fatty acids; it also increases colonic lactobacilli and bifidobacteria.
• Crystal formulation: One gram of lactulose crystals is equivalent to 1.5 mL of the oral solution.
• Retention enema preparation: For acute hepatic encephalopathy, dilute lactulose with 2–3 parts warm water before administration as a retention enema; beforehand, give a cleansing enema of warmed polyionic (crystalloid) fluid, 10–15 mL/kg, until the return is clear (in people, cleansing enemas containing soap suds or other alkaline agents should not be used).
• Clinical response: The therapeutic effect depends on bacterial metabolism within the colon; therefore, individual response may vary.
• Product availability: Lactulose is available as an oral solution (10 g/15 mL) and as crystals for oral solution (10 g and 20 g packets); there are no veterinary-labeled products.
• Storage: Store the solution at room temperature (20–25°C; 68–77°F), protected from light in tight containers, and do not freeze; normal darkening does not affect potency, but extremely dark or cloudy solutions should be discarded, and crystals that precipitate dissolve with gentle warming.
• Pharmacokinetics: In people, less than 3% of an oral dose is absorbed, and the absorbed drug is excreted unchanged in the urine within 24 hours.
• Onset of effect: In people, lactulose does not act until it reaches the colon and colonic transit may be slow, so 24 to 48 hours may be needed to produce a bowel movement; in people with portal-systemic encephalopathy, improvement in the patient’s condition may occur within 24 hours but may not begin before 48 hours or even later.
• Evidence: One reference describes the uses of lactulose in small animals as resting on anecdotal observations and expert recommendations; in a randomized trial in dogs with congenital extrahepatic portosystemic shunts before surgery, clinical scores had fallen at 4 weeks on a hepatic diet plus lactulose but not on the diet alone or the diet plus metronidazole, and in a study of 78 dogs with congenital shunts managed without surgery, the estimated median survival time did not differ significantly between an adjusted diet alone and the diet plus lactulose, although the sample was small and lactulose use and doses varied.
• Alternative disaccharide: For animals that dislike the taste, lactitol, a similar synthetic disaccharide, can be given as a powder in food, although its efficacy in hepatic encephalopathy has not been extensively evaluated.
• Client advice: Advise owners to contact the veterinarian if diarrhea develops or, when lactulose is used for hepatic encephalopathy, if signs worsen or fewer than 2–3 soft stools are produced each day; train owners to give enemas to abate acute-onset hepatic encephalopathy.