GIT Lec 6 - Biliary System

Question 1

What is the predominant benign disease affecting the biliary system?

Answer 1

The predominant diseases affecting the biliary system are chronic cholestatic diseases, including:
1. Primary Sclerosing cholangitis (PSC)
2. Primary biliary cirrhosis (PBS)
3. Gallstones
4. Pure intra-hepatic cholestasis

Question 2

What are the primary drugs used in the treatment of PSC, PBC, gallstones and PIHC?

Answer 2

1. Bile acid
2. Ursodeoxycholic Acid (UDCA) (Ursodiol)
3. Chenodeoxycholic Acid (CDCA) (Chenodiol)
4. Copper chelating agents

Question 3

Bile acid therapy is divided into two types, what are they?

Answer 3

A. Displacement therapy:
The main goal of displacement therapy is to alter the composition of bile acid pool in order to decrease the cytotoxicity of the endogenous bile acid.
B. Replacement therapy:
The main goal of replacement therapy is to replenish or correct bile acid deficiency due to bile acid malabsorption or short bowel syndrome.

Question 4

What is Ursodeoxycholic acid?

Answer 4

It’s a naturally occurring bile acid that is found in small amounts in human bile. It’s taken as an oral agent to dissolve cholesterol stones. It’s taken with or after food, and the gal stone dissolution can take up to several months or it may not even occur at all.

Question 5

What are the pharmacokinetics of Ursodiol?

Answer 5

1. It is well absorbed after being taken orally, and then passes into the portal circulation where it undergoes first-pass metabolism leaving very little amount of it to enter the systemic circulation.
2. The recommended dose of Ursodiol is 13-15mg/kg/day (in 3 or 4 doses) in patients with PSC and PBC, or 10-15mg/kg/day in patients with gallstones.

Question 6

What are the pre-requisites that should be taken into consideration before giving Ursodiol?

Answer 6

1. The patient should be in a symptomatic stage with no complications
2. Patent cystic bile duct and good gall bladder emptying should be found on ultrasound
3. The stone should be translucent on X-ray, and less than 5mm in size.

Question 7

When do we discontinue Ursodiol therapy?

Answer 7

We discontinue the therapy when there’s either no partial response within 6 months or no complete response with 24 months (2 years).

Question 8

What is the major caveat (disadvantage) of Ursodiol?

Answer 8

Stone reoccurrence in 3-5 years after discontinuing the therapy has been observed in 30-50% of patients treated with Ursodiol

Question 9

What are the contraindications of Ursodiol?

Answer 9

1. Patients that are allergic to the drug
2. Existence of calcified gallstones
3. IBD
4. Patients that require cholecystoctomy

Question 10

What are the characteristics of chenodeoxycholic acid?

Answer 10

1. It’s a primary bile acid in humans and it’s effective in dissolving gallstones in some patients.
2. The efficacy of chenodeoxycholic acid is reduced if administered simultaneously with cholestyramine, colestipol or aluminum antacids.

Question 11

What are the indications of chenodiol?

Answer 11

It’s suitable for the treating of gallstones in patients unresponsive to other means, who have mild symptoms, unimpaired gallbladder function, and small-medium sized translucent gallstones.

Question 12

What is the MOA of chenodiol?

Answer 12

It inhibits the rate-limiting enzyme of the conversion of bile salts into cholesterol; that is HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl Co-enzyme A reductase) thus resulting in:
1. Increased bile salt excretion
2. Decreased cholesterol secretion
It also causes feedback inhibition of bile acid synthesis.
It’s action begins with half an hour and up to 12 hours, with the maximum beneficial effect reached within 18 months

Question 13

What is the dosing for chonediol?

Answer 13

It is given in a dose of 10-15mg/kg daily as a single dose or in divided doses for approx. 3-24 months depending on the size of the stone.
The treatment is continued for three months after the stone dissolution.

Question 14

What are the adverse effects of chenodiol?

Answer 14

The use of CDCA is limited by its adverse effects which include:
1. Diarrhea, in up to 30% of patients
2. Increased aminotransferase levels in a similar percentage to diarrhea
3. Pruritus

Question 15

What are the contraindications of CDCA?

Answer 15

1. Allergy to the drug
2. Bile tract obstruction
3. GIT blockage
4. Pregnancy
5. Cirrhosis & pancreatitis

Question 16

What is most practical and cost-effective method of treating gallstones?

Answer 16

Laparoscopic cholecystoctomy.

Question 17

In which cases do we prefer the use of Ursodiol over conventional surgery?

Answer 17

1. When cholecystoctomy is contraindicated
2. In patients who wish to avoid surgery

Question 18

What are examples of bile acid sequestrants?

Answer 18

1. Cholestyramine
2. Colestipol
3. Colesevelam

Question 19

What is the MOA of bile acid-binding resins?

Answer 19

1. Bile acid sequestrants are positively charged polymeric resins that bind to the negatively charged bile acids and bile salts in the intestinal lumen
2. This binding results in the formation of a resin-bile salt complex which is then excreted in feces
3. This leads to a decrease in the concentration of bile salts, which stimulates the hepatocytes to increase the conversion of cholesterol into bile salts which replenishes the bile salts which are an important part of bile.
4. As a result of that conversion, intra-cellular concentrations of cholesterol drop which promotes re-uptake of cholesterol-containing LDL molecules by the liver.

Question 20

What are the indications of acid-binding resins?

Answer 20

1. At first they were used for the treatment of hypercholesterolaemia but was later found to be useful in hepatic and intestinal disorders
2. It can be used to prevent diarrhea by binding with free bile salts in patients with mild bile salt malabsorption
3. It’s been used to decrease pruritus in patients with cholestasis; presumably by decreasing the concentration of the bile acids in the systemic circulation

Question 21

What are the pharmacokinetics of acid-binding resins?

Answer 21

1. Their efficacy is moderate because of the weak bile acid binding capacity of the resins
2. They are taken orally and excreted in feces

Question 22

What are the adverse effects of bile acid-binding resins?

Answer 22

1- Constipation, nausea, and flatulence. Colesevelam has fewer side effect than others.

2- At high doses, cholestyramine and colestipol impair the absorption of fat soluble vitamins.

Question 23

What are the drug interactions of bile-acid binding resins?

Answer 23

Cholestyramine and colestipol interfere with the intestinal absorption of many drugs like (tetracycline, Phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin and thiazide diuretics).
Therefore, drugs should be taken at least 1-2 hours before, or 4-6 hours after, the bile acid-binding resins.