Ursodeoxycholic acid is an epimer of chenodeoxycholic acid .Ursodiol is a synthetically-derived form of ursodiol, a bile acid produced by the liver and secreted and stored in the gallbladder. Also produced by the Chinese black bear liver, ursodiol has been used in the treatment of liver disease for centuries. This agent dissolves or prevents cholesterol gallstones by blocking hepatic cholesterol production and decreasing bile cholesterol. Ursodiol also reduces the absorption of cholesterol from the intestinal tract.
It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic.Primary bile acids are produced by the liver and stored in the gall bladder. When secreted into the colon, primary bile acids can be metabolized into secondary bile acids by intestinal bacteria. Primary and secondary bile acids help the body digest fats. Ursodeoxycholic acid helps regulate cholesterol by reducing the rate at which the intestine absorbs cholesterol molecules while breaking up micelles containing cholesterol.
Drug Interactions of ursodeoxycholic acid
Ursodiol is administered orally. Only small amounts of ursodiol appear in the systemic circulation and very small amounts are excreted into the urine. With repeated dosing, bile ursodiol concentrations reach a steady-state in about 3 weeks; ursodiol concentrations in the bile do not exceed 60% of the total bile acid pool. After ursodiol is discontinued, the concentration of the drug in bile falls exponentially, declining to roughly 5—10% of its steady-state level within 1 week.
Beyond conjugation, ursodiol is not catabolized appreciably by the liver or intestinal mucosa. A small proportion of the orally administered drug undergoes bacterial degradation in the intestine with each cycle of enterohepatic circulation. rsodiol can be both oxidized and reduced, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Further, the conjugated glyco- or tauro-ursodiol may be deconjugated in the small bowel, yielding free ursodiol. All of these bacterial degradation products are relatively insoluble and large proportions of these products are excreted in the feces. Some free ursodiol is reabsorbed and reconjugated by the liver. Eighty-percent of the lithocholic acid formed in the small bowel is excreted in the feces, but 20% is reabsorbed and then sulfated by the liver to lithocholyl conjugates excreted in the bile and lost in the feces. Small amounts of 7-keto-lithocholic acid are reabsorbed and stereospecifically reduced by the liver to chenodiol.
Indications of ursodeoxycholic acid
- The drug reduces cholesterol absorption and is used to dissolve (cholesterol) gallstones in patients who want an alternative to surgery.
- Primary Biliary Cirrhosis
- Gallstone formation
- Nonalcoholic Fatty Liver Disease
- Biliary Cirrhosis
- Gallbladder Disease
- Cystic fibrosis
- Treatment of primary biliary cirrhosis
- Treatment of dissolution of small to medium sized radiolucent,
- Cholesterol-rich gall-stones
- Reduction in gallstone formation, either in patients with gallstones unfit for cholecystectomy, or obese patients undergoing rapid weight loss to prevent gallstone formation.
- For the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis, PBC).
- To aim to improve bile flow in patients with cystic fibrosis (controversial)
- In newborn infants with impaired bile flow
- After bariatric surgery, to prevent cholelithiasis due to the rapid weight loss with biliary cholesterol oversaturation and also biliary diskinesia secondary to abnormalities in cholecystokinin and biliary enervation.
Contra indications of ursodeoxycholic acid
- Radio-opaque calcified gall-stones,
- Inflammation of the gall bladder or biliary tracts
- Occlusion of the biliary tract (occlusion of the common bile duct or a cystic duct)
- Frequent episodes of biliary colic
- Impaired contractability of the gall bladder
- Hypersensitivity to bile acids or any excipient of the formulation
- Pregnant or breastfeeding, or in women who may become pregnant.
- Chronic liver disease, peptic ulcers or in those with inflammatory diseases of the small intestine and colon.
-
Presence of calcified gallstone
-
Patients requiring cholecystectomy
Dosages of ursodeoxycholic acid
- Strengths: 250 mg; 300 mg; 500mg
Gallstones,
- 6—12mg/kg daily (max 15mg/kg daily in obese patients) in two divided doses after meals or once daily at night for up to 2 years.
- Continue for 3—4 months after the dissolution of stones.
Children: Gallstones or biliary cirrhosis,
Cystic fibrosis, under 6 years, not recommended;
- 6-18years initially 20mg/kg daily in two or three divided doses increased to 30mg/kg daily if necessary.
Gallbladder Disease
Capsules:
- Gallbladder stone dissolution: 8 to 10 mg/kg/day orally in 2 or 3 divided doses
- Gallstone prevention: 300 mg orally twice a day
Biliary Cirrhosis
- Tablets:13 to 15 mg/kg/day orally in 2 to 4 divided doses with food
Pediatric Dose for Gallbladder Disease
(Not approved by FDA)
Some experts recommend
Parenteral nutrition-induced cholestasis in neonates
- 30 mg/kg/day orally in 3 divided doses; some centers divide in 2 daily doses
Biliary atresia
- Infants: 10 to 15 mg/kg orally once a day
Treatment of TPN-induced cholestasis
- Infants and children: 30 mg/kg/day orally in 3 divided doses
Side Effects of Ursodeoxycholic acid
The most common
-
Bloody and cloudy urine
-
Black or tarry stools
-
Unusual bleeding or bruising
More common
- Bladder pain
- bloody or cloudy urine
- difficult, burning, or painful urination
- dizziness
- fast heartbeat
- frequent urge to urinate
- indigestion
- lower back or side pain
- severe nausea
- skin rash or itching over the entire body
- stomach pain
- vomiting
- weakness
Less common
- Abnormal vision, including difficulty with adjusting to distances
- bloody or cloudy urine
- difficult, burning, or painful urination
- frequent urge to urinate
- Sensation of pins and needles in the fingers and toes
- Allergic reactions
- Nervousness
- Aware of the heartbeat (palpitations)
- Heart failure
- Irregular heartbeat
- Heart burn
- Memory impairment
Rare
- Clay-colored stools
- dark urine
- difficulty with swallowing
- headache
- large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
- loss of appetite
- redness of the skin
- slow or irregular breathing
- tightness in the chest
Drug Interactions of ursodeoxycholic acid
- antacids containing aluminum
- cholestryramine
- clofibrate
- colestipol
- medications that lower cholesterol levels
- medications that contain estrogen, including birth control pills
- Aluminum Hydroxide: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
- Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
- Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
- Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
- Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
- Charcoal: (Major) Activated charcoal, which is available in dietary supplements, has been shown to adsorb bile acids in vitro and is expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. Concurrent use is not recommended.
- Cholestyramine: (Moderate) Cholestyramine may interfere with the action of ursodeoxycholic acid, ursodiol by reducing its absorption. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 4 to 6 hours after the bile acid sequestering agents.
- Ciprofloxacin: (Moderate) There has been one case report of reduced serum concentrations of ciprofloxacin after the administration of ursodeoxycholic acid, ursodiol to a patient with hepatobiliary disease. The mechanism of the proposed interaction is uncertain.
- Colesevelam: (Moderate) Colesevelam may interfere with the action of ursodeoxycholic acid, ursodiol by reducing its absorption. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 4 hours after the bile acid sequestering agents.
- Colestipol: (Moderate) Colestipol may interfere with the action of ursodeoxycholic acid, ursodiol by reducing its absorption. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 4 hours after the bile acid sequestering agents.
- Estrogens: (Minor) Estrogens and combined hormonal and oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation, and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
- Fenofibrate: (Major) Fibric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
- Fenofibric Acid: (Major) Fibric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
- Fibric acid derivatives: (Major) Fabric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
- Gemfibrozil: (Major) Fibric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
This is not a complete list of ursodiol drug interactions. Ask your doctor or pharmacist for more information.
Pregnancy & lactation ursodeoxycholic acid
FDA pregnancy category B
Ursodiol is classified in FDA pregnancy risk category B. Animal studies have revealed no evidence of impaired fertility or harm to the fetus due to ursodiol. There are no adequate or well-controlled studies in pregnant women; use during pregnancy only if clearly needed. Ursodiol has been used effectively and safely in women with intrahepatic cholestasis of pregnancy (ICP) in several clinical trials; current evidence is insufficient to definitively determine maternal or fetal safety;
Lactation
Women of childbearing potential should be treated only if they are using reliable contraception: non-hormonal or low-estrogen oral contraceptive measures are recommended. However, in patients taking ursodeoxycholic acid for dissolution of gallstones, effective non-hormonal contraception should be used, since hormonal oral contraceptives may increase biliary lithiasis. The possibility of a pregnancy must be excluded before beginning treatment.
It is not known whether ursodeoxycholic acid passes into breast milk. Therefore, the ursodeoxycholic acid should not be taken during lactation. If treatment with ursodeoxycholic acid is necessary, breastfeeding must be discontinued.
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