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

1338 Loperamide N-oxide, an investigational agent, is a site-specific
prodrug; it is chemically designed for controlled release of loperamide
in the intestinal lumen, thereby reducing systemic absorption.
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Diphenoxylate and Difenoxin. Diphenoxylate and its
active metabolite difenoxin (diphenoxylic acid) are
piperidine derivatives that are related structurally to
meperidine. As anti-diarrheal agents, diphenoxylate and
difenoxin are somewhat more potent than morphine.
Both compounds are extensively absorbed after oral administration,
with peak levels achieved within 1-2 hours. Diphenoxylate
is rapidly deesterified to difenoxin, which is eliminated with a t 1/2
of
~12 hours. Both drugs can produce CNS effects when used in higher
doses (40-60 mg per day) and thus have a potential for abuse and/or
addiction. They are available in preparations containing small doses
of atropine (considered subtherapeutic) to discourage abuse and
deliberate overdosage: 25 μg of atropine sulfate per tablet with either
2.5 mg diphenoxylate hydrochloride (LOMOTIL) or 1 mg of difenoxin
hydrochloride (MOTOFEN). The usual dosage is two tablets initially,
then one tablet every 3-4 hours, not to exceed eight tablets per day.
With excessive use or overdose, constipation and (in inflammatory
conditions of the colon) toxic megacolon may develop. In high
doses, these drugs cause CNS effects as well as anticholinergic
effects from the atropine (dry mouth, blurred vision, etc.) (Chapter 9).
Other opioids used for diarrhea include codeine (in doses
of 30 mg given three or four times daily) and opium-containing
compounds. Paregoric (camphorated opium tincture) contains the
equivalent of 2 mg of morphine per 5 mL (0.4 mg/mL); deodorized
tincture of opium, which is 25 times stronger, contains the equivalent
of 50 mg of morphine per 5 mL (10 mg/mL). The two tinctures
sometimes are confused in prescribing and dispensing, resulting in
dangerous overdoses. The anti-diarrheal dose of opium tincture for
adults is 0.6 mL (equivalent to 6 mg morphine) four times daily; the
adult dose of paregoric is 5-10 mL (equivalent to 2-4 mg morphine)
one to four times daily. Paregoric is used in children at a dose of
0.25-0.5 mL/kg (equivalent to 0.1-0.2 mg morphine/kg) one to four
times daily.
Enkephalins are endogenous opioids that are important
enteric neurotransmitters. Enkephalins inhibit intestinal secretion
without affecting motility. Racecadotril (acetorphan), a dipeptide
inhibitor of enkephalinase, reinforces the effects of endogenous
enkephalins on the δ-opioid receptor to produce an anti-diarrheal
effect.
α 2
Adrenergic Receptor Agonists. α 2
Adrenergic receptor agonists
such as clonidine can interact with specific receptors on enteric neurons
and enterocytes, thereby stimulating absorption and inhibiting
secretion of fluid and electrolytes and increasing intestinal transit
time. These agents may have a special role in diabetics with chronic
diarrhea, in whom autonomic neuropathy can lead to loss of noradrenergic
innervation. Oral clonidine (beginning at 0.1 mg twice a
day) has been used in these patients; the use of a topical preparation
(e.g., CATAPRES TTS, two patches a week) may result in more steady
plasma levels of the drug. Clonidine also may be useful in patients
with diarrhea caused by opiate withdrawal. Side effects such as
hypotension, depression, and perceived fatigue may be dose limiting
in susceptible patients.
Octreotide and Somatostatin. Octreotide (SANDOSTATIN,
others) (Chapter 43) is an octapeptide analog of
somatostatin (SST) that is effective in inhibiting the
severe secretory diarrhea brought about by hormonesecreting
tumors of the pancreas and the GI tract. Its
mechanism of action appears to involve inhibition of
hormone secretion, including 5-HT and various other
GI peptides (e.g., gastrin, vasoactive intestinal polypeptide
(VIP), insulin, secretin, etc.). Octreotide has been
used off label, with varying success, in other forms of
secretory diarrhea such as chemotherapy-induced diarrhea,
diarrhea associated with human immunodeficiency
virus (HIV), and diabetes-associated diarrhea.
Its greatest utility, however, may be in the “dumping
syndrome” seen in some patients after gastric surgery
and pyloroplasty. In this condition, octreotide inhibits
the release of hormones (triggered by rapid passage of
food into the small intestine) that are responsible for
distressing local and systemic effects.
Octreotide has a t 1/2
of 1-2 hours and is administered either
subcutaneously or intravenously as a bolus dose. Standard initial
therapy with octreotide is 50-100 μg, given subcutaneously two or
three times a day, with titration to a maximum dose of 500 μg three
times a day based on clinical and biochemical responses. A longacting
preparation of octreotide acetate enclosed in biodegradable
microspheres (SANDOSTATIN LAR DEPOT) is available for use in the
treatment of diarrheas associated with carcinoid tumors and
VIP–secreting tumors, as well as in the treatment of acromegaly
(Chapter 44). This preparation is injected intramuscularly once per
month in a dose of 20 or 30 mg. Side effects of octreotide depend on
the duration of therapy. Short-term therapy leads to transient nausea,
bloating, or pain at sites of injection. Long-term therapy can
lead to gallstone formation and hypo- or hyperglycemia. Another
long-acting SST analog, lanreotide (SOMATULIN, others), is available
in Europe but not in the U.S.; another, vapreotide, is under development.
SST (STILAMIN) also is available in Europe.
Variceal Bleeding. Vasoactive agents have been used to control variceal
bleeding. Traditionally, vasopressin has been used (Chapter 26), but
its significant side effects—such as myocardial ischemia, peripheral
vascular disease, and the release of plasminogen activator and factor
VIII—have led to its decline. SST and octreotide are effective in
reducing hepatic blood flow, hepatic venous wedge pressure, and azygos
blood flow. These agents constrict the splanchnic arterioles by a
direct action on vascular smooth muscle and by inhibiting the release
of peptides contributing to the hyperdynamic circulatory syndrome of
portal hypertension. Octreotide also may act through the autonomic
nervous system. These agents can control bleeding acutely and
decrease bleeding-related mortality, with an efficacy comparable to
endoscopic therapy or balloon tamponade. The major advantage of
somatostatin and octreotide over vasopressin is their safety. Because
of its short t 1/2
(1-2 minutes), SST can be given only by intravenous
infusion (a 250 μg bolus dose followed by 250 μg hourly for 5 days).
Higher doses (up to 500 μg/hour) are more efficacious and can be
used for patients who continue to bleed on the lower dose (Moitinho