DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

R3
Bile Acid
Cholic acid
R12
CH 3
CH 3
R3
–OH
R7
R7
–OH
R12
–OH
Chenodeoxycholic acid
Deoxycholic acid
–OH
–OH
–OH
–H
–H
–OH
Lithocholic acid –SO – 2 / –OH –H –H
Ursodeoxycholic acid –OH OH –H
Figure 46–5. Major bile acids in adults.
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feedback-inhibit cholesterol synthesis, promote intestinal
excretion of cholesterol, and facilitate the dispersion
and absorption of lipids and fat-soluble vitamins.
After secretion into the biliary tract, bile acids are
largely (95%) reabsorbed in the intestine (mainly in the
terminal ileum), returned to the liver, and then again
secreted in bile (enterohepatic circulation). Cholic acid,
chenodeoxycholic acid, and deoxycholic acid constitute
95% of bile acids; lithocholic acid and ursodeoxycholic
acid are minor constituents. The bile acids exist
largely as glycine and taurine conjugates, the salts of
which are called bile salts. Colonic bacteria convert primary
bile acids (cholic and chenodeoxycholic acid) to
secondary acids (mainly deoxycholic and lithocholic
acid) by sequential deconjugation and dehydroxylation.
These secondary bile acids also are absorbed in the colon
and join the primary acids in the enterohepatic pool.
Dried bile from the Himalayan bear (Yutan) has been used
for centuries in China to treat liver disease. Ursodeoxycholic acid
(UDCA; ursodiol, ACTIGALL, others) (Figure 46–5) is a hydrophilic,
dehydroxylated bile acid that is formed by epimerization of the bile
acid chenodeoxycholic acid (CDCA; chenodiol) in the gut by intestinal
bacteria; it comprises ~1-3% of the total bile acid pool in human
beings but is present at much higher concentrations in bears. When
administered orally, litholytic bile acids such as chenodiol and ursodiol
can alter relative concentrations of bile acids, decrease biliary lipid
secretion, and reduce the cholesterol content of the bile so that it is less
lithogenic. Ursodiol also may have cytoprotective effects on hepatocytes
and effects on the immune system that account for some of its
beneficial effects in cholestatic liver diseases.
Bile acids were first used therapeutically for gallstone dissolution;
use for this indication requires a functional gallbladder
C
O
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glycine (75%)
taurine (24%)
–OH (<1%)
because the modified bile must enter the gallbladder to interact with
gallstones. To be amenable to dissolution, the gallstones must be
composed of cholesterol monohydrate crystals and generally must be
<15 mm in diameter to provide a favorable ratio of surface to size.
For these reasons, the overall efficacy of litholytic bile acids in the
treatment of gallstones has been disappointing (partial dissolution
occurs in 40-60% of patients completing therapy and is complete in
only 33-50% of these). Although a combination of chenodiol and
ursodiol probably is better than either agent alone, ursodiol is preferred
as a single agent because of its greater efficacy and lessfrequent
side effects (e.g., hepatotoxicity).
Primary biliary cirrhosis is a chronic, progressive, cholestatic
liver disease of unknown etiology that typically affects middleaged
to elderly women. Ursodiol (administered at 13-15 mg/kg per
day in two divided doses) reduces the concentration of primary bile
acids and improves biochemical and histological features of primary
biliary cirrhosis, especially in early disease. Patients with advanced
primary biliary cirrhosis and complications such as ascites do not
benefit from this treatment. Ursodiol also has been used in a variety
of other cholestatic liver diseases, including primary sclerosing
cholangitis, and in cystic fibrosis; in general, it is less effective in
these conditions than in primary biliary cirrhosis.
ANTI-FLATULENCE AGENTS
“Gas” is a common but relatively vague GI complaint,
used in reference not only to flatulence and eructation
but also bloating or fullness. Although few symptoms
can be directly attributable to excessive intestinal gas,
over-the-counter and herbal preparations that are touted
as anti-flatulent are very popular. One of these is simethicone
(MYLICON, GAS-x, others), a mixture of siloxane
polymers stabilized with silicon dioxide.
H 3 C
H 3 C
CH 3
Simethicone is an inert, non-toxic insoluble liquid. Because
of its ability to collapse bubbles by forming a thin layer on their surface,
it is an effective anti-foaming agent. Although it may be effective
in diminishing gas volumes in the GI tract, it is not clear whether
this accomplishes a therapeutic effect. Simethicone is available in
chewable tablets, liquid-filled capsules, suspensions, and orally disintegrating
strips, either by itself or in combination with other overthe-counter
medications including antacids and other digestants. The
usual dosage in adults is 40-25 mg four times daily. Activated charcoal
may also be used alone or in combination with simethicone, but
has not been shown conclusively to have much benefit.
An alpha-galactosidase preparation (BEANO) is available overthe-counter
to reduce gas from baked beans.
CLINICAL SUMMARY
Si OSi CH 3 + SiO 2
H 3 C CH 3
GI Motility Disorders. As a group, these are difficult
disorders to treat because of a lack of effective therapeutic
n
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CHAPTER 46
TREATMENT OF DISORDERS OF BOWEL MOTILITY AND WATER FLUX