Gastrointestinal Drugs

Drugs for Dissolving Gallstones (A)
Following its secretion from liver into
bile, water-insoluble cholesterol is held
in solution in the form of micellar complexes
with bile acids and phospholipids.
When more cholesterol is secreted
than can be emulsified, it precipitates
and forms gallstones (cholelithiasis).
Precipitated cholesterol can be reincorporated
into micelles, provided the cholesterol
concentration in bile is below
saturation. Thus, cholesterol-containing
stones can be dissolved slowly. This
effect can be achieved by long-term oral
administration of chenodeoxycholic
acid (CDCA) or ursodeoxycholic acid
(UDCA). Both are physiologically occurring,
stereoisomeric bile acids (position
of the 7-hydroxy group being ! in UCDA
and " in CDCA). Normally, they represent
a small proportion of the total
amount of bile acid present in the body
(circle diagram in A); however, this increases
considerably with chronic administration
because of enterohepatic
cycling, p. 38). Bile acids undergo almost
complete reabsorption in the ileum.
Small losses via the feces are made up
by de novo synthesis in the liver, keeping
the total amount of bile acids constant
(3–5 g). Exogenous supply removes
the need for de novo synthesis of
bile acids. The particular acid being supplied
gains an increasingly larger share
of the total store.
The altered composition of bile increases
the capacity for cholesterol uptake.
Thus, gallstones can be dissolved
in the course of a 1- to 2 y treatment,
provided that cholesterol stones are
pure and not too large (<15 mm), gall
bladder function is normal, liver disease
is absent, and patients are of normal
body weight. UCDA is more effective
(daily dose, 8–10 mg) and better tolerated
than is CDCA (15 mg/d; frequent
diarrhea, elevation of liver enzymes in
plasma). Stone formation may recur after
cessation of successful therapy.
Compared with surgical treatment,
drug therapy plays a subordinate role.
UCDA may also be useful in primary biliary
cirrhosis.
Choleretics are supposed to stimulate
production and secretion of dilute
bile fluid. This principle has little therapeutic
significance.
Cholekinetics stimulate the gallbladder
to contract and empty, e.g., egg
yolk, the osmotic laxative MgSO4, the
cholecystokinin-related ceruletide (given
parenterally). Cholekinetics are employed
to test gallbladder function for
diagnostic purposes.
Pancreatic enzymes (B) from
slaughtered animals are used to relieve
excretory insufficiency of the pancreas
(! disrupted digestion of fats; steatorrhea,
inter alia). Normally, secretion of
pancreatic enzymes is activated by
cholecystokinin/pancreozymin, the enterohormone
that is released into blood
from the duodenal mucosa upon contact
with chyme. With oral administration
of pancreatic enzymes, allowance
must be made for their partial inactivation
by gastric acid (the lipases, particularly).
Therefore, they are administered
in acid-resistant dosage forms.
Antiflatulents (carminatives) serve
to alleviate meteorism (excessive accumulation
of gas in the gastrointestinal
tract). Aborad propulsion of intestinal
contents is impeded when the latter are
mixed with gas bubbles. Defoaming
agents, such as dimethicone (dimethylpolysiloxane)
and simethicone, in combination
with charcoal, are given orally
to promote separation of gaseous and
semisolid contents.