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

et al., 2001). For patients with variceal bleeding, therapy with
octreotide usually is initiated while the patient is awaiting endoscopy.
Intestinal Dysmotility. Octreotide has complex and apparently conflicting
effects on GI motility, including inhibition of antral motor
activity and colonic tone. However, octreotide also can rapidly
induce phase III activity of the migrating motor complex in the small
bowel to produce longer and faster contractions than those occurring
spontaneously. Its use has been shown to result in improvement
in selected patients with scleroderma and small-bowel dysfunction.
Pancreatitis. Both SST and octreotide inhibit pancreatic secretion
and have been used for the prophylaxis and treatment of acute pancreatitis.
The rationale for their use is to “put the pancreas to rest”
so as to not aggravate inflammation by the continuing production of
proteolytic enzymes, to reduce intraductal pressures, and to ameliorate
pain. Octreotide probably is less effective than SST in this
regard because it may cause an increase in sphincter of Oddi pressure
and perhaps also have a deleterious effect on pancreatic blood
flow. Although some studies have suggested that these agents
improve mortality in patients with acute pancreatitis, definitive data
are lacking.
Other Agents
Calcium channel blockers such as verapamil and nifedipine
(Chapters 25 and 27) reduce motility and may promote intestinal
electrolyte and water absorption. Constipation, in fact, is a significant
side effect of these drugs. However, because of their systemic effects
and the availability of other agents, they seldom if ever are used for
diarrheal illnesses.
Berberine is a plant alkaloid that has been used for millennia
in traditional Indian and Chinese medicine. It is produced by
several genera of the families Ranuculaceae and Berberidaceae
(e.g., Berberis, Mahonia, and Coptis) and has complex pharmacological
actions that include antimicrobial actions, stimulation of
bile flow, inhibition of ventricular tachyarrhythmias, and possible
antineoplastic activity. It is used most commonly in bacterial diarrhea
and cholera, but is also apparently effective against intestinal
parasites. The anti-diarrheal effects in part may be related to its
antimicrobial activity, as well as its ability to inhibit smooth muscle
contraction and delay intestinal transit by antagonizing the
effects of ACh (by competitive and noncompetitive mechanisms)
and blocking the entry of Ca 2+ into cells. In addition, it inhibits
intestinal secretion.
Chloride channel blockers are effective anti-secretory
agents in vitro but are too toxic for human use and have not proven
to be effective anti-diarrheal agents in vivo. Calmodulin inhibitors,
which include chlorpromazine, also are anti-secretory. Zaldaride
maleate, an investigational drug in this class, may be effective in
traveler’s diarrhea by reducing secretion without affecting intestinal
motility.
IRRITABLE BOWEL SYNDROME (IBS)
IBS, a condition that affects up to 15% of the population
in the U.S., is perhaps one of the more challenging
nonfatal illnesses seen by gastroenterologists (Mertz,
2003). Patients may complain of a variety of symptoms,
the most characteristic of which is recurrent abdominal
pain associated with altered bowel movements. The
pathophysiology of this condition is not clear; it appears
to result from a varying combination of disturbances in
visceral motor and sensory function, often associated
with significant affective disorders. The disturbances in
bowel function, which can be either constipation or
diarrhea or both at different times, have led to the classical
interpretation of IBS as being a “motility disorder,”
but motor disturbances cannot explain the entire
clinical picture. Recently, more emphasis has been
devoted to the pathogenesis of pain in these patients,
and there now is considerable evidence to suggest a
specific enhancement of visceral (as opposed to
somatic) sensitivity to noxious, as well as physiological
stimuli in this syndrome. The etiopathogenesis of this
visceral hypersensitivity probably is multifactorial; a
popular hypothesis is that transient visceral injury in
genetically predisposed individuals leads to longlasting
sensitization of the neural pain circuit despite
complete resolution of the initiating event. Increasingly,
this concept is being extended to other so-called functional
disorders of the gut characterized by unexplained
pain, including noncardiac chest pain and nonulcer dyspepsia.
These disorders, also considered for many years
to arise from motor disturbances, may in fact represent
part of a spectrum of a new syndrome of “visceral
hyperalgesia.”
Many patients can be managed satisfactorily with a strong
patient-physician relationship, simple counseling, and adjunctive
measures, including dietary restrictions and fiber supplementation;
overt psychological abnormalities should be treated appropriately.
Despite these measures, a significant proportion of patients remain
plagued by severe symptoms, and drug therapy is attempted almost
invariably. However, there are very few effective pharmacological
options for these patients, a situation that in part reflects our limited
understanding of the pathogenesis of this syndrome.
The pharmacological approach to IBS reflects its multifaceted
nature. Treatment of bowel symptoms (either diarrhea or constipation)
is predominantly symptomatic and nonspecific. Patients
with mild symptoms often are started on fiber supplements; this
approach may work for constipation and diarrhea (by binding
water). Patients with episodic, discrete pain episodes often are
treated with agents that may reduce smooth muscle contractility in
the gut. These so-called antispasmodics include anticholinergic
agents, Ca 2+ channel antagonists, and peripheral opioid receptor
antagonists. The use of most such drugs is hallowed by years of tradition
but seldom has been subjected to critical assessment; however,
these drugs may be modestly effective in a subset of patients
and are useful adjuncts.
In recent years, an increasing emphasis is being placed on the
pharmacological treatment of visceral sensitivity. Although the biological
basis of visceral hyperalgesia in IBS patients is not known,
a possible role for serotonin has been suggested based on its known
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CHAPTER 46
TREATMENT OF DISORDERS OF BOWEL MOTILITY AND WATER FLUX