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

1346 component of nausea and vomiting in patients. For a detailed discussion
of these drugs, see Chapter 17.
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Phosphorated Carbohydrate Solutions
Aqueous solutions of glucose, fructose, and phosphoric acid
(EMETROL, NAUSETROL) are available over the counter to relieve nausea.
Their mechanism of action is not well established. They may be
safely taken for a short period (1 hour with a dose every 15 minutes).
AGENTS USED FOR MISCELLANEOUS
GI DISORDERS
Chronic Pancreatitis and Steatorrhea
Pancreatic Enzymes. Chronic pancreatitis is a debilitating
syndrome that results in symptoms from loss of
glandular function (exocrine and endocrine) and inflammation
(pain). Because there is no cure for chronic pancreatitis,
the goals of pharmacological therapy are
prevention of malabsorption and palliation of pain. The
cornerstone of therapy for malabsorption is the use of
pancreatic enzymes. Although also used for pain, these
agents are much less effective for this symptom.
Enzyme Formulations. In the past, two preparations (and many brands
thereof) of pancreatic enzymes were available for replacement therapy,
pancreatin and pancrelipase. As of 2009, only pancrelipase
(CREON, ZENPEP) is licensed for sale in the U.S. Pancreatic enzymes
are typically prescribed on the basis of the lipase content.
Pancrelipase products contain various amounts of lipase, protease,
and amylase and thus may not be interchangeable. Excess lipase
administration has been implicated in the development of fibrosing
colonopathy and adherence to published dosing guidelines is thought
to minimize this risk (Borowitz et al., 2002).
Replacement Therapy for Malabsorption. Fat malabsorption (steatorrhea)
and protein maldigestion occur when the pancreas loses >90%
of its ability to produce digestive enzymes. The resultant diarrhea
and malabsorption can be managed reasonably well if 30,000 USP
units of pancreatic lipase are delivered to the duodenum during a
4-hour period with and after meals; this represents ~10% of the normal
pancreatic output. Alternatively, one can titrate the dosage to the
fat content of the diet, with ~8000 USP units of lipase activity
required for each 17 g of dietary fat. Available preparations of pancreatic
enzymes contain up to 20,000 units of lipase and 76,000 units
of protease, and the typical dose of pancrelipase is one to three capsules
or tablets with or just before meals and snacks, adjusted until
a satisfactory symptomatic response is obtained. The loss of pancreatic
amylase does not present a problem because of other sources of
this enzyme (e.g., salivary glands). The commercially available products
are formulated as delayed-release capsules to overcome the need
to control gastric acid pharmacologically.
Enzymes for Pain. Pain is the other cardinal symptom of chronic pancreatitis.
The rationale for its treatment with pancreatic enzymes is
based on the principle of negative feedback inhibition of the pancreas
by the presence of duodenal proteases. The release of cholecystokinin
(CCK), the principal secretagogue for pancreatic enzymes,
is triggered by CCK-releasing monitor peptide in the duodenum,
which normally is denatured by pancreatic trypsin. In chronic pancreatitis,
trypsin insufficiency leads to persistent activation of this
peptide and an increased release of CCK, which is thought to cause
pancreatic pain because of continuous stimulation of pancreatic
enzyme output and increased intraductal pressure. Delivery of active
proteases to the duodenum (which can be done reliably only with
uncoated preparations) therefore is important for the interruption of
this loop. Although enzymatic therapy has become firmly entrenched
for the treatment of painful pancreatitis, the evidence supporting this
practice is equivocal at best.
In general, pancreatic enzyme preparations are tolerated
extremely well by patients. Hyperuricosuria in patients with cystic
fibrosis can occur, and malabsorption of folate and iron has been
reported.
Medium-chain triglycerides. Medium-chain triglycerides (MCTs)
may provide an additional source of calories in patients with weight
loss and a poor response to diet and pancreatic enzyme therapy.
MCTs are readily degraded by gastric and pancreatic lipase, and they
do not require bile for digestion. In addition, they can be directly
absorbed in the intestine. Oral administration of an enteral formula
such as PEPTAMEN, which is enriched in MCTs and hydrolyzed peptides,
may be of benefit.
Octreotide. Octreotide (Chapter 38) also has been used, with questionable
efficacy, to decrease refractory abdominal pain in patients
with chronic pancreatitis.
Enzyme Deficiencies
Congenital or acquired deficiencies in digestive enzymes may lead
to malabsorption and diarrhea as well as other GI symptoms. Most
commonly seen are lactose intolerance, which occurs in the West
(10-20%) but in some Asian populations may exceed 90%.
Clinically, diarrhea, pain and flatulence occur. Treatment consists of
reducing dietary intake of lactose, primarily by reducing consumption
of milk and dairy products. Enzyme replacements are over the
counter and can be added to meals. They are bacterial or yeastderived
β-galactosidases, with varying efficacy (LACTAID, LACTRASE,
DAIRYEASE, others). Because of considerable individual variation and
the uncertain degree of efficacy of these preparations, patients must
establish an effective dosing regime empirically. Because of the
essential requirements to maintain protein, calcium, and vitamin D
intake, these must be supplemented or alternative sources provided
in the diet if dairy products are limited.
Congenital sucrase-isomaltase deficiency is less common. The
symptoms include diarrhea, abdominal pain, and weight loss. This is
a congenital disease and may be diagnosed in children who are failing
to thrive and are susceptible to repeated infections. Treatment with
enzyme replacement therapy is effective. Sacrosidase (SUCRAID) taken
with meals reduces or attenuates symptoms in most cases. Elimination
of sugars and carbohydrates from the diet is not practical.
BILE ACIDS
Bile acids and their conjugates are essential components
of bile that are synthesized from cholesterol in
the liver. The major bile acids in human adults are
depicted in Figure 46–5. Bile acids induce bile flow,