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

In patients suspected of having bile salt–induced diarrhea, a trial
of cholestyramine (QUESTRAN, QUESTRAN LIGHT, others) can be given at
a dose of 4 g of the dried resin (four times a day). If successful, the dose
may be titrated down to achieve the desired stool frequency.
Cholestyramine resin also is helpful for the relief of pruritus
associated with partial biliary obstruction and in conditions such as primary
biliary cirrhosis. In such conditions, excessive bile acids are
thought to be deposited in the skin and cause irritation. Cholestyramine
increases fecal excretion of bile acids and reduces circulating and eventually
systemic levels with relief of pruritus in ~1-3 weeks.
Bismuth. Bismuth compounds have been used to treat
a variety of GI diseases and symptoms for centuries,
although their mechanism of action remains poorly
understood. PEPTO-BISMOL (or generic formulations of
bismuth subsalicylate) is an over-the-counter preparation
estimated to be used by 60% of American households.
It is a crystal complex consisting of trivalent
bismuth and salicylate suspended in a mixture of magnesium
aluminum silicate clay. In the low pH of the
stomach, the bismuth subsalicylate reacts with
hydrochloric acid to form bismuth oxychloride and salicylic
acid. Although 99% of the bismuth passes unaltered
and unabsorbed into the feces, the salicylate is
absorbed in the stomach and small intestine. Thus, the
product carries the same labeled warning regarding
Reye’s syndrome as other salicylates, and patients taking
other forms of salicylates should be made aware of
the overlap in adverse effect.
Bismuth is thought to have anti-secretory, anti-inflammatory,
and antimicrobial effects. Nausea and abdominal cramps also are
relieved by bismuth. The clay in PEPTO-BISMOL and generic formulations
also may have some additional benefits in diarrhea, but this
is not clear. Bismuth subsalicylate has been used extensively for the
prevention and treatment of traveler’s diarrhea, but it also is effective
in other forms of episodic diarrhea and in acute gastroenteritis.
Today, the most common antibacterial use of this agent is in the treatment
of Helicobacter pylori (Chapter 45). A recommended dose of
the bismuth subsalicylate (30 mL of regular strength liquid or two
tablets) contains approximately equal amounts of bismuth and salicylate
(262 mg each). For control of indigestion, nausea, or diarrhea,
the dose is repeated every 30-60 minutes, as needed, up to eight
times a day. Bismuth products have a long track record of safety at
recommended doses, although impaction may occur in infants and
debilitated patients. Dark stools (sometimes mistaken for melena)
and black staining of the tongue in association with bismuth compounds
are caused by bismuth sulfide formed in a reaction between
the drug and bacterial sulfides in the GI tract.
Probiotics. The GI tract contains a vast commensal microflora that
is necessary for health. Alterations in the balance or composition of
the microflora are responsible for antibiotic-associated diarrhea, and
possibly other disease conditions. The administration of nonpathogenic
bacteria to recolonize the gut is an area of intense investigation
(Sartor, 2005). Probiotic preparations containing a variety of bacterial
strains have shown some degree of benefit in acute diarrheal
conditions, antibiotic-associated diarrhea, and infectious diarrhea,
but most clinical studies have been small and conclusions are therefore
limited. Because these agents are generally safe, their use continues
despite mainly anecdotal evidence of efficacy.
Anti-Motility and Anti-Secretory Agents
Opioids. Opioids continue to be widely used in the
treatment of diarrhea. They act by several different
mechanisms, mediated principally through either μ- or
δ-opioid receptors on enteric nerves, epithelial cells,
and muscle (Chapter 18). These mechanisms include
effects on intestinal motility (μ receptors), intestinal
secretion (δ receptors), or absorption (μ and δ receptors).
Commonly used anti-diarrheals such as diphenoxylate,
difenoxin, and loperamide act principally via
peripheral μ opioid receptors and are preferred over
opioids that penetrate the CNS.
Loperamide. Loperamide (IMODIUM, IMODIUM A-D, others),
a piperidine butyramide derivative with μ receptor
activity, is an orally active anti-diarrheal agent. The
drug is 40-50 times more potent than morphine as an
anti-diarrheal agent and penetrates the CNS poorly. It
increases small intestinal and mouth-to-cecum transit
times. Loperamide also increases anal sphincter tone,
an effect that may be of therapeutic value in some
patients who suffer from anal incontinence. In addition,
loperamide has anti-secretory activity against cholera
toxin and some forms of Escherichia coli toxin, presumably
by acting on G i
-linked receptors and countering
the increase in cellular cyclic AMP generated in
response to the toxins.
Because of its effectiveness and safety, loperamide is marketed
for over-the-counter distribution and is available in capsule, solution,
and chewable tablet forms. It acts quickly after an oral dose, with peak
plasma levels achieved within 3-5 hours. It has a t 1/2
of ~11 hours and
undergoes extensive hepatic metabolism. The usual adult dose is 4 mg
initially followed by 2 mg after each subsequent loose stool, up to 16 mg
per day. If clinical improvement in acute diarrhea does not occur
within 48 hours, loperamide should be discontinued. Recommended
maximum daily doses for children are 3 mg for ages 2-5 years, 4 mg
for ages 6-8 years, and 6 mg for ages 8-12 years. Loperamide is not
recommended for use in children <2 years of age.
Loperamide has been shown to be effective against traveler’s
diarrhea, used either alone or in combination with antimicrobial
agents (trimethoprim, trimethoprim-sulfamethoxazole, or a fluoroquinolone).
Loperamide also has been used as adjunct treatment in
almost all forms of chronic diarrheal disease, with few adverse
effects. Loperamide lacks significant abuse potential and is more
effective in treating diarrhea than diphenoxylate. Overdosage, however,
can result in CNS depression (especially in children) and paralytic
ileus. In patients with active inflammatory bowel disease
involving the colon (Chapter 47), loperamide should be used with
great caution, if at all, to prevent development of toxic megacolon.
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CHAPTER 46
TREATMENT OF DISORDERS OF BOWEL MOTILITY AND WATER FLUX