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

effluent is clear. To avoid net transfer of ions across the
intestinal wall, these preparations contain an isotonic
mixture of sodium sulfate, sodium bicarbonate, sodium
chloride, and potassium chloride. The osmotic activity
of the PEG molecules retains the added water and the
electrolyte concentration assures little or no net ionic
shifts.
PEGs (without electrolytes) are also increasingly being
used in smaller doses (250-500 mL daily) for the treatment of constipation
in difficult cases. A powder form of polyethylene glycol
3350 (MIRALAX, others) is now available for the short-term treatment
(≤2 weeks) of occasional constipation, although the agent
has been prescribed safely for longer periods in clinical practice.
The usual dose is 17 g of powder per day in 8 ounces of water.
This preparation does not contain electrolytes, so larger volumes
may represent a risk for ionic shifts. As with other laxatives, prolonged,
frequent, or excessive use may result in dependence or
electrolyte imbalance.
Stool-Wetting Agents and Emollients
Docusate salts are anionic surfactants that lower the
surface tension of the stool to allow mixing of aqueous
and fatty substances, softening the stool and permitting
easier defecation. However, these agents also stimulate
intestinal fluid and electrolyte secretion (possibly by
increasing mucosal cyclic AMP) and alter intestinal
mucosal permeability. Docusate sodium (diocytl
sodium sulfosuccinate; COLACE, DOXINATE, others) and
docusate calcium (dioctyl calcium sulfosuccinate;
SURFAK, others), are available in several dosage forms.
Despite their widespread use, these agents have marginal,
if any, efficacy in most cases of constipation.
Mineral oil is a mixture of aliphatic hydrocarbons obtained
from petrolatum. The oil is indigestible and absorbed only to a
limited extent. When mineral oil is taken orally for 2-3 days, it
penetrates and softens the stool and may interfere with resorption
of water. The side effects of mineral oil preclude its regular use
and include interference with absorption of fat-soluble substances
(such as vitamins), elicitation of foreign-body reactions in the
intestinal mucosa and other tissues, and leakage of oil past the
anal sphincter. Rare complications such as lipid pneumonitis due
to aspiration also can occur, so “heavy” mineral oil should not be
taken at bedtime and “light” (topical) mineral oil should never be
administered orally.
Stimulant (Irritant) Laxatives
Stimulant laxatives have direct effects on enterocytes,
enteric neurons, and GI smooth muscle. These agents
probably induce a limited low-grade inflammation in the
small and large bowel to promote accumulation of water
and electrolytes and stimulate intestinal motility. Proposed
mechanisms include activation of prostaglandin–cyclic
AMP and NO–cyclic GMP pathways, platelet-activating
factor production (see earlier), and inhibition of Na + , K + -
ATPase. Included in this group are diphenylmethane
derivatives, anthraquinones, and ricinoleic acid.
Diphenylmethane Derivatives. Bisacodyl (DULCOLAX,
CORRECTOL, others) is the only diphenylmethane derivative
available in the U.S. It is marketed as entericcoated
and regular tablets and as a suppository for rectal
administration.
The usual oral daily dose of bisacodyl is 10-15 mg for adults
and 5-10 mg for children ages 6-12 years old. The drug requires
hydrolysis by endogenous esterases in the bowel for activation, and
so the laxative effects after an oral dose usually are not produced in
<6 hours; taken at bedtime, it will produce its effect the next morning.
Suppositories work much more rapidly, within 30-60 minutes.
Due to the possibility of developing an atonic nonfunctioning colon,
bisacodyl should not be used for >10 consecutive days.
Bisacodyl is mainly excreted in the stool; ~5% is absorbed
and excreted in the urine as a glucuronide. Overdosage can lead to
catharsis and fluid and electrolyte deficits. The diphenylmethanes
can damage the mucosa and initiate an inflammatory response in the
small bowel and colon. To avoid drug activation in the stomach with
consequent gastric irritation and cramping, patients should swallow
tablets without chewing or crushing and avoid milk or antacid medications
within 1 hour of the ingestion of bisacodyl.
Phenolphthalein, once among the most popular components
of laxatives, has been withdrawn from the market in the U.S. because
of potential carcinogenicity. Oxyphenisatin, another older drug, was
withdrawn due to hepatotoxicity. Sodium picosulfate (LUBRILAX,
SUR-LAX) is a diphenylmethane derivative widely available outside of
the U.S. It is hydrolyzed by colonic bacteria to its active form, and
hence acts locally only in the colon. Effective doses of the diphenylmethane
derivatives vary as much as 4- to 8-fold in individual
patients. Consequently, recommended doses may be ineffective in
some patients but may produce cramps and excessive fluid secretion
in others.
Anthraquinone Laxatives. These derivatives of plants
such as aloe, cascara, and senna share a tricyclic
anthracene nucleus modified with hydroxyl, methyl, or
carboxyl groups to form monoanthrones, such as rhein
and frangula. Monoanthrones are irritating to the oral
mucosa; however, the process of aging or drying converts
them to more innocuous dimeric (dianthrones) or
glycoside forms. This process is reversed by bacterial
action in the colon to generate the active forms.
Senna (SENOKOT, EX-LAX, others) is obtained from the dried
leaflets on pods of Cassia acutifolia or Cassia angustifolia and contains
the rhein dianthrone glycosides sennoside A and B. Cascara
sagrada is obtained from the bark of the buckthorn tree and contains
the glycosides barbaloin and chrysaloin. Barbaloin is also found in
aloe. The rhubarb plant also produces anthraquinone compounds that
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CHAPTER 46
TREATMENT OF DISORDERS OF BOWEL MOTILITY AND WATER FLUX