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

visceral pain (Eutamene et al., 2009), a major factor
in IBS-C.
Opioid-Induced Constipation
Opioids are the main class of analgesics in the treatment
and palliation of cancer, as well as other chronic pain
states. Opioids cause severe constipation, which significantly
limits their acceptability and reduces quality of
life considerably. Laxatives and dietary strategies are
frequently ineffective in the management of opioidinduced
constipation. A promising strategy is the prevention
of opioid-induced constipation with peripherally
acting μ opioid receptor antagonists that specifically target
the underlying reason for this condition, without limiting
centrally produced analgesia. Methylnaltrexone
(RELISTOR) was approved for the treatment of opioidinduced
constipation by the FDA in 2008. Approval was
based on multicenter trials demonstrating good efficacy
in initiating bowel movements after injection of the drug
in end-stage cancer patients in a hospice setting. When
methylnaltrexone (0.15-0.3 mg/kg) was administered
repeatedly every other day for 2 weeks, bowel movements
occurred in 50% of the patients, compared with
8–15% of patients receiving placebo (Holzer, 2009).
Another μ opioid antagonist, alvimopan (ENTEREG,
0.5-1 mg twice daily for 6 weeks) has also been tested
in this setting where it increased spontaneous bowel
movements and improved other symptoms of opioidinduced
constipation without compromising analgesia
(Holzer, 2009). Opioid-induced constipation represents
an off-label use for alvimopan.
Post-operative Ileus
Post-operative ileus refers to the intolerance to oral
intake and non-mechanical obstruction of the bowel
that occurs after abdominal and non-abdominal surgery.
It generally lasts 1-3 days after surgery with some variation
along the length of the bowel. The pathogenesis is
complex and is a combination of activation of neural
inhibitory reflexes involving enteric μ opioid receptors
and the activation of local inflammatory mechanisms
that reduce smooth muscle contractility. The condition
is exacerbated by opioids, which are the mainstay of
post-operative analgesia. The extent to which endogenous
opioids are involved in post-operative ileus remains to
be determined. Prolonged post-operative ileus is hard
to treat, and therefore considerable efforts are made to
prevent its occurrence, including use of epidural anesthetics,
minimally invasive surgeries, and reduced narcotic
administration. Prokinetic agents typically do not
have much effect in this condition, but recently, two
new therapeutic agents have been introduced that have
benefit in reducing GI recovery time after surgery.
Alvimopan (ENTEREG) is an orally active peripherally
restricted μ opioid receptor antagonist that is
FDA approved for limited indications following surgery
(12 mg prior to surgery and then once daily for up
to 7 days or until discharge; not to exceed 15 doses
total). Methylnaltrexone (RELISTOR) is another peripherally
restricted μ opioid receptor antagonist that lacks
anti-analgesic actions. Methylnaltrexone reportedly
enhanced GI transit but did not reduce time to discharge
compared to standard approaches (Holzer, 2009). It is
FDA approved for the treatment of opioid-induced constipation
in patients receiving palliative care when laxative
therapy is insufficient.
Dexpanthenol (ILOPAN, others) is the alcohol of
pantothenic acid (vitamin B 5
). The drug is a congener
of pantothenic acid, a precursor of coenzyme A, which
serves as a cofactor in the synthesis of ACh by choline
acetyl transferase. It is proposed to act by enhancing
ACh synthesis. ACh is the major excitatory transmitter
of the gut. Dexpanthenol is used as an injection immediately
postoperatively after major abdominal surgery
to minimize the occurrence of paralytic ileus. It is given
by intramuscular injection (200-500 mg) immediately
and then 2 hours later and every 6 hours after that until
the situation has resolved. It may cause mild hypotension
and shortness of breath as well as local irritation.
Enemas and Suppositories
Enemas commonly are employed, either by themselves or as
adjuncts to bowel preparation regimens, to empty the distal colon or
rectum of retained solid material. Bowel distention by any means
will produce an evacuation reflex in most people, and almost any
form of enema, including normal saline solution, can achieve this.
Specialized enemas contain additional substances that are either
osmotically active or irritant; however, their safety and efficacy have
not been studied in a rigorous manner. Repeated enemas with tap
water or other hypotonic solutions can cause hyponatremia; repeated
enemas with sodium phosphate–containing solution can cause
hypocalcemia. Phosphate-containing enemas also are known to alter
the appearance of rectal mucosa and contribute to acute phosphate
nephropathy in susceptible patients.
Glycerin is a trihydroxy alcohol that is absorbed orally but
acts as a hygroscopic agent and lubricant when given rectally. The
resultant water retention stimulates peristalsis and usually produces
a bowel movement in less than an hour. Glycerin is for rectal use
only and is given in a single daily dose as a 2- or 3-g rectal suppository
or as 5-15 mL of an 80% solution in enema form. Rectal glycerin
may cause local discomfort, burning, or hyperemia and
(minimal) bleeding. Some glycerin suppositories contain sodium
stearate, which can cause local irritation.
Another agent for occasional constipation makes use of rectal
distension to initiate laxation. CEO-TWO suppositories contain
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CHAPTER 46
TREATMENT OF DISORDERS OF BOWEL MOTILITY AND WATER FLUX