CASE 33
A 48-year-old woman presents for evaluation of abdominal pain. She reports that she gets right upper-abdominal pain after eating. It is worse if she eats fatty or fried food. She has tried over-the-counter antacids without relief. She has no significant medical history, has had no surgeries, and takes no medications on a regular basis. Both her mother and an older sister have had to have their gallbladders removed. On examination, she is moderately obese, but her examination is otherwise normal. An abdominal x-ray is normal. An ultrasound of her abdomen reveals several small gallstones. You diagnose her with cholelithiasis and recommend surgical evaluation. She is adamant in wanting to do anything to avoid surgery, so you prescribe ursodiol.
What is the mechanism of action of ursodiol?
How long does it take to see full effect of this medication?
What effect does ursodiol have on low-density lipoprotein (LDL) cholesterol levels?
ANSWERS TO CASE 33:
Drugs Used to Dissolve Gallstones
Summary: A 48-year-old woman presents with cholelithiasis. She does not desire surgery, and is prescribed ursodiol.
Mechanism of action of ursodiol: Reduces cholesterol secretion into bile.
Length of time to see full effect: Months to years.
Effect on LDL cholesterol levels: No change.
CLINICAL CORRELATION
Gallstones are a common cause of abdominal pain. These often consist of a high proportion of cholesterol, which is excreted from the liver into bile. The bile is taken up in the gallbladder, where the cholesterol may precipitate into stones. Ursodiol is ursodeoxycholic acid, a bile acid. It reduces cholesterol secretion into bile with little change in the secretion of bile acid. It is used in an effort to dissolve cholesterol gallstones in patients who either do not want surgery or are not surgical candidates. The full effect of this medication can take from several months to years. It is also used as an adjunct to shock wave lithotripsy of gallstones. In this treatment, sound waves are used to break gallstones into small fragments. Ursodiol may then be used to attempt to dissolve the fragments. Radiopaque gallstones, which contain calcium, are not effectively dissolved with ursodiol. It is administered orally, and its side effects are primarily GI, with nausea and diarrhea being common. Ursodiol does not alter LDL cholesterol levels in the blood.
APPROACH TO:
Pharmacology of Agents Used to Dissolve Gallstones
OBJECTIVES
1. Know the drugs used to dissolve gallstones and their mechanism of action.
2. Know the routes of administration and side effects of these drugs.
DEFINITIONS
Cholelithiasis: The presence of stones in the gallbladder or common bile duct, or the process of formation of such stones.
Cholecystitis: Inflammation of the gallbladder.
Lithotripsy: Reduction of gallstones, using sound waves, to small particles that can be excreted from the gallbladder.
DISCUSSION
Class
Gallstones are a major cause of morbidity and mortality, and surgical removal of the gallbladder is among the most common GI surgeries. Although surgical removal is the preferred treatment, other treatments, including ultrasound lithotripsy or pharmacologic dissolution, are therapeutic options in patients who cannot have surgery. Gallstones can be transported into the duodenum and block the exit of the pancreatic duct, causing pancreatitis. Gallstones can be radiotranslucent, indicating a stone high in cholesterol content, or radiopaque, indicating a stone with significant mineral (usually calcium) content. Ursodeoxycholic acid (ursodiol) is a naturally occurring bile acid that is a minor component of bile. It has been used successfully to treat relatively small, radiotranslucent stones, especially those within the common bile duct. It decreases the synthesis of bile and reduces the concentration of cholesterol in bile. Ursodiol solubilizes cholesterol by forming bile acid micelles and disperses liquid crystals of cholesterol in an aqueous environment. These actions will slowly cause the dissolution of the gallstone. Complete dissolution occurs in approximately 30 percent of patients with stones less than 20 mm in diameter. It also decreases the biliary colic that is associated with gallstones in some patients. The prophylactic administration of ursodiol caused a marked reduction in the incidence of gallstones after cardiac surgery. Older approaches to pharmacologic dissolution of gallstones employed organic solvents such as methyl-tert-butyl ether (MTBE) or monoglycerides such as monooctanoin. Although rapid dissolution of gallstones could be achieved, leakage of the solvent materials into the lumen of the bowel was associated with serious adverse effects, and these approaches have been largely discontinued. Adverse effects of ursodiol are minor, typically GI upset and mild diarrhea. Since bile supersaturation with cholesterol is a key factor for cholesterol gallstone formation, the lipid-lowering drug ezetimibe (see Case 13) reduces cholesterol concentration in plasma and in bile by inhibiting cholesterol secretion and may be useful in reducing the size and occurrence of gallstones.
Structure
Ursodiol is derived from 7-hydroxycholesterol and is a naturally occurring component in bile.
Administration
Ursodiol is administered orally, two to three times a day, and complete dissolution of stones may require a year. Treatment effectiveness should be monitored by diagnostic ultrasound.
COMPREHENSION QUESTIONS
33.1 Ursodiol reduces the size of common bile duct gallstones by which of the following mechanisms?
A. Chelating Ca2+ out of the stone
B. Decreasing the synthesis of bile
C. Increasing the cholesterol content in bile
D. Slowly dissolving cholesterol from the stone
33.2 A 35-year-old woman is noted to have cholelithiasis. She opts for medical therapy with ursodiol. Complete dissolution of a gallstone by ursodiol typically requires how long?
A. Several hours
B. Weeks
C. Months to years
D. Several years
33.3 Ursodiol has been useful to treat which of the following conditions?
A. Cholestasis of pregnancy
B. Cirrhosis
C. Diabetes mellitus
D. Pancreatitis resulting from trauma
ANSWERS
33.1 D. Ursodiol is a detergent that slowly causes dissolution of gallstones that are rich in cholesterol. It decreases the amount of cholesterol in bile as well as total bile acid synthesis.
33.2 C. Ursodiol treatment typically takes months to a year for dissolution of a typical gallstone.
33.3 A. Ursodeoxycholic acid has been used successfully to treat the symptoms of pruritus associated with cholestasis of pregnancy, a disease thought to be caused by the accumulation of bile salts.
PHARMACOLOGY PEARLS
Ursodiol is the best nonsurgical therapy for small, radiotranslucent gallstones in patients who are not candidates for surgery.
Ursodeoxycholic acid has also been used to treat cholestasis of pregnancy.
REFERENCES
Portincasa P, Ciaula AD, Bonfrate L, Wang DQ. Therapy of gallstone disease: what it was, what it is, what it will be. World J Gastrointest Pharmacol Ther. 2012;3:7–20.
Di Ciaula A, Wang DQ, Wang HH, Bonfrate L, Portincasa P. Targets for current pharmacologic therapy in cholesterol gallstone disease. Gastroenterol Clin North Am. 2010;39:245–64.
Tuncer I, Harman M, Colak Y, Arslan I, Turkdogan MK. Effect of ursodeoxycholic acid alone and ursodeoxycholic acid plus domperidone on radiolucent gallstones and gallbladder contractility in humans. Gastroenterol Res Pract. 2012;159438.