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Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in Gastrointestinal Disorders

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Drugs That Decrease GI Motility

Diarrhea is the frequent passage of watery, unformed stools. Its many causes include IBS, infectious disorders, thyrotoxicosis, malabsorption, medication side effect, and laxative abuse.

DRUGS THAT DECREASE GI MOTILITY

Diarrhea is the frequent passage of watery, unformed stools. Its many causes include IBS, infectious disorders, thyrotoxicosis, malabsorption, medication side effect, and laxative abuse. Attempts to treat diarrhea should first fo-cus on the patient’s list of medications followed by a search for an underlying systemic disorder. Opioids and 5-HT3 receptor antagonists, such as alosetron, slow motil-ity and can therefore decrease or eliminate diarrhea.

Opioids

Most of the opioids have a constipating action; mor-phine was used in the treatment of diarrhea before it was used as an analgesic. Unfortunately, many of the opium preparations, while relieving diarrhea and dysentery, also produce such objectionable side effects as respiratory depression and habituation . The opioids are capable of altering the motility pat-tern in all parts of the GI tract. These compounds usu-ally produce an increase in segmentation and a de-crease in the rate of propulsive movement. The feces become dehydrated as a result of their longer stay in the GI tract. The tone of the internal anal sphincter is increased, and the subjective response to the stimulus of a full rectum is reduced by the central action of the opioids. All of these actions produce constipation. Opioids should not be used indiscriminately in bloody diarrhea, since their use in inflammatory bowel disease involving the colon may increase the risk of megacolon and their use in infectious enterocolitis may promote intestinal perforation.

The dangers of dependency and addiction clearly preclude the use of such compounds as morphine, meperidine, and methadone as treatment for diarrhea. Antidiarrheal specificity therefore is of paramount im-portance in choosing among the synthetic opioids and their analogues (e.g., diphenoxylate and loperamide).

Diphenoxylate (marketed in combination with at-ropine as Lomotil in the United States) is chemically re-lated to both analgesic and anticholinergic compounds. It is as effective in the treatment of diarrhea as the opium derivatives, and at the doses usually employed, it has a low incidence of central opioid actions. Diphen-oxylate is rapidly metabolized by ester hydrolysis to the biologically active metabolite difenoxylic acid. Lomotil is recommended as adjunctive therapy in the manage-ment of diarrhea. It is contraindicated in children under 2 years old and in patients with obstructive jaundice. Adverse reactions often caused by the atropine in the preparation include anorexia, nausea, pruritus, dizzi-ness, and numbness of the extremities.

Loperamide hydrochloride (Imodium) structurally resembles both haloperidol and meperidine. In equal doses, loperamide protects against diarrhea longer than does diphenoxylate. It reduces the daily fecal volume and decreases intestinal fluid and electrolyte loss. Loperamide produces rapid and sustained inhibition of the peristaltic reflex through depression of longitudinal and circular muscle activity. The drug also possesses an-tisecretory activity, presumably through an effect on in-testinal opioid receptors. Loperamide is effective against a wide range of secretory stimuli and can be used in the control and symptomatic relief of acute di-arrhea that is not secondary to bacterial infection. Adverse effects associated with its use include abdomi-nal pain and distention, constipation, dry mouth, hyper-sensitivity, and nausea and vomiting.

 

Tincture of opium (10% opium) is a rapidly acting preparation for the symptomatic treatment of diarrhea.

The more widely used paregoric (camphorated opium tincture) is equally effective and is frequently used in combination with other antidiarrheal agents. Codeine also has been used for short-term symptomatic treat-ment.

Alosetron

Alosetron (Lotronex) is a 5-HT3 receptor antagonist. Blocking this receptor results in decreased GI motility. Alosetron received FDA approval in February 2000 for the treatment of women with diarrhea-predominant IBS. In November 2000, at the request of the FDA, the drug was voluntarily withdrawn due to reported cases of ischemic colitis, including some fatalities.

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