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

1334 have been used as laxatives. Anthraquinones can also be synthesized;
however, the synthetic monoanthrone danthron was withdrawn from
the U.S. market because of concerns over possible carcinogenicity.
In addition, all aloe and cascara sagrada products sold as laxatives
have been categorized by FDA as not generally recognized as safe
and effective for over-the-counter use because of a lack of scientific
information about potential carcinogenicity.
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Although these ingredients may still be sold overthe-counter
in the U.S., legally they cannot be labeled
for use as laxatives. This judgment is medically prudent
but may provoke a longing for times past in Joyceans,
who recall that cascara sagrada, the sacred bark, worked
well for Leopold Bloom, in Dublin, on June 16, 1904:
Midway, his last resistance yielding, he allowed
his bowels to ease themselves quietly as he read,
reading still patiently that slight constipation of
yesterday quite gone. Hope its not too big to bring
on piles again. No, just right. So. Ah! Costive one
tabloid of cascara sagrada. Life might be so.
(Joyce, 1922)
Anthraquinone laxatives can produce giant migrating
colonic contractions and induce water and electrolyte secretion.
They are poorly absorbed in the small bowel, but because they
require activation in the colon, the laxative effect is not noted until
6-12 hours after ingestion. Active compounds are absorbed to a
variable degree from the colon and excreted in the bile, saliva,
milk, and urine.
The adverse consequences of long-term use of these agents
have limited their use. A melanotic pigmentation of the colonic
mucosa (melanosis coli) has been observed in patients using
anthraquinone laxatives for long periods (at least 4-9 months).
Histologically, this is caused by the presence of pigment-laden
macrophages within the lamina propria. The condition is benign and
reversible on discontinuation of the laxative. These agents also have
been associated with the development of “cathartic colon,” which
can be seen in patients (typically women) who have a long-standing
history (typically years) of laxative abuse. Regardless of whether a
definitive causal relationship can be demonstrated between the use
of these agents and colonic pathology, it is clear that they should not
be recommended for chronic or long-term use.
Castor Oil. A bane of childhood since the time of the ancient
Egyptians, castor oil (PURGE, NEOLOID, others) is derived from the bean
of the castor plant, Ricinus communis. The castor bean is the source of
an extremely toxic protein, ricin, as well as the oil (chiefly of the
triglyceride of ricinoleic acid). The triglyceride is hydrolyzed in the
small bowel by the action of lipases into glycerol and the active agent,
ricinoleic acid, which acts primarily in the small intestine to stimulate
secretion of fluid and electrolytes and speed intestinal transit. When
taken on an empty stomach, as little as 4 mL of castor oil may produce
a laxative effect within 1-3 hours; however, the usual dose for a cathartic
effect is 15-60 mL for adults. Because of its unpleasant taste and
its potential toxic effects on intestinal epithelium and enteric neurons,
castor oil is seldom recommended now.
Prokinetic and Other Agents
for Constipation
Although several of the agents already described stimulate
motility, they do so in nonspecific or indirect
ways. By contrast, the term prokinetic generally is
reserved for agents that enhance GI transit via interaction
with specific receptors involved in the regulation of
motility.
Newer agents, such as the potent 5-HT 4
-receptor agonist
prucalopride, may be useful for the treatment of chronic constipation.
Another potentially useful agent is misoprostol, a synthetic
prostaglandin analog primarily used for protection against gastric
ulcers resulting from the use of NSAIDs (Chapters 34 and 45).
Prostaglandins can stimulate colonic contractions, particularly in the
descending colon, and this may account for the diarrhea that limits
the usefulness of misoprostol as a gastroprotectant. However, this
property may be utilized for therapeutic gain in patients with
intractable constipation. Colchicine, a microtubule formation
inhibitor used for gout (Chapter 34), also has been shown to be effective
in constipation (mechanism unknown), but its toxicity has limited
widespread use. A novel biological agent, neurotrophin-3
(NT-3), recently was shown to be effective in improving frequency
and stool consistency and decreasing straining, again by an unknown
mechanism of action.
A new development in the treatment of constipation
is the introduction of drugs that enhance fluid secretion
by acting locally on ion channels in the colonic
epithelium, to promote secretion. Lubiprostone (AMITIZA)
is a prostanoid activator of Cl − channels. The drug
appears to bind to EP 4
receptors linked to activation of
adenylyl cyclase, leading to enhanced apical Cl − conductance;
the identity of the Cl − channel(s) involved is
not certain, possibly CFTR and CIC-2. Lubiprostone
was recently introduced for treatment of chronic constipation
in adults and irritable bowel syndrome with constipation
(IBS-C) in adult women. The drug promotes
the secretion of a chloride-rich fluid and so improves
stool consistency and promotes increased frequency by
reflexly activating motility. A dose of 8 μg twice daily
was found to be effective in IBS-C, though higher doses
(24 μg twice daily) is given for chronic constipation.
The drug is poorly bioavailable, acting only in the lumen
of the bowel. Side effects of lubiprostone include nausea,
headache, diarrhea, allergic reactions, and dyspnea.
Another class of secretory agent is represented by
linaclotide, a 14–amino acid peptide agonist of guanylate
cyclase C that stimulates secretion and motility.
This compound shows promise in the treatment of
IBS-C and chronic constipation, and it appears to have
few serious side effects (Gale, 2009). Recent work in
rodents suggests it may also be antinociceptive, reducing