Gallstone Dissolving Drugs

GALLSTONE  DISSOLVING  DRUGS

Cholesterol (CH) remains dissolved in bile with the help of bile salts (salts of cholic acid and chenodeoxycholic acid conjugated with glycine and taurine) because bile salts are highly amphiphilic. A high CH : bile salt ratio favours crystallization of CH in bile; these crystals act as nidi for stone formation. Chenodeoxycholic acid (Chenodiol) and Ursodeoxycholic acid (Ursodiol) decrease CH content of bile, enabling solubilization of CH from stone surface. These two bile acids act differently.

Chenodiol

In a dose of 10–15 mg/kg/day it has been found to partially or completely dissolve CH gallstones in about 40% patients over 1/2 to 2 years. However, only 1/3 of these had complete dissolution. Pigment stones and calcified stones (15–20% cases) are not affected.

Side Effects:

Diarrhoea occurs in nearly half of the patients. It is dose-related and generally mild.

Raised aminotransferase level is also common and dose-related, but overt liver damage occurs in only 3% patients. It is reversible.

Gastric and esophageal mucosal resistance to acid is impaired favouring ulceration.

Ursodiol

It is a hydroxy epimer of chenodiol, is more effective and needs to be used at lower doses (7–10 mg/ kg/day). Complete dissolution of CH stones has been achieved in upto 50% cases. It is also much better tolerated. Diarrhoea and hyper-transaminaemia are infrequent, but effect on mucosal resistance is similar to chenodiol. Calcification of some gall stones may be induced.

Dose: 450–600 mg daily in 2–3 divided doses after meals; UDCA, UDIHEP 150 mg tab.

Dissolution of gallstones is a very slow process: patient compliance is often poor. However, medical treatment is now possible in selected patients:

·  Only CH stones (radiolucent, generally multiple stones that float on oral cholecystography) are amenable.

·           Smaller stones respond better; therapy is not indicated if stone is > 15 mm in diameter.

·          Gallbladder should be functional. If bile is not entering gallbladder, it will not be able to solubilize the stones.

·    Contraindicated in pregnant women and those likely to conceive (foetal damage possible).

Efficacy of these drugs is enhanced by a single daily bedtime dose and by low CH diet. Concurrent lithotripsy speeds dissolution rate. Because chenodiol and ursodiol act differently, their combination at 1/2 of the individual doses is more effective and attended with fewer adverse effects. However, ursodiol alone is the preferred drug.

Another method of achieving quick dissolution is direct instillation of liquid ether, methyl-terbutyl ether into the gallbladder through a percutaneous pigtail catheter.

Once treatment is discontinued after stone dissolution, recurrences are common, because bile returns to its CH supersaturated state. Repeat courses may have to be given. Because of these problems the pros and cons of medical therapy must be weighed against cholecystectomy.

Other uses: Bile salts and bile acids have been used as replacement therapy in cholestasis, biliary fistula and liver disease. They are a constituent of many combination formulations. Ursodiol, because it is not hepatotoxic, may be useful in cirrhosis and some other hepatic disorders.