Introduction
Diarrhoea is the passage of loose or watery stool at least three times within a 24-hour period. Dehydration and malnutrition are the two main issues that arise from diarrhoea especially in children.
An appreciation and knowledge of the underlying causative processes in diarrhea facilitates effective treatment. From a mechanistic perspective, diarrhea can be caused by an increased osmotic load within the intestine (resulting in retention of water within the lumen); excessive secretion of electrolytes and water into the intestinal lumen; exudation of protein and fluid from the mucosa; and altered intestinal motility resulting in rapid transit (and decreased fluid absorption). In most instances, multiple processes are affected simultaneously, leading to a net increase in stool volume and weight accompanied by increases in fractional water content. Many patients with sudden onset of diarrhea have a benign, self-limited illness requiring no treatment or evaluation.
In severe cases, dehydration and electrolyte imbalances are the principal risk, particularly in infants, children, and frail elderly patients. Oral rehydration therapy therefore is a cornerstone for patients with acute illnesses resulting in significant diarrhea. This is of particular importance in developing countries, where the use of such therapy saves many thousands of lives every year. This therapy exploits the fact that nutrient-linked cotransport of water and electrolytes remains intact in the small bowel in most cases of acute diarrhea. Sodium and chloride absorption is linked to glucose uptake by the enterocyte; this is followed by movement of water in the same direction. A balanced mixture of glucose and electrolytes in volumes matched to losses therefore can prevent dehydration. This can be provided by many commercial premixed formulas using glucose-electrolyte or rice-based physiological solutions.
Pharmacotherapy of diarrhea should be reserved for patients with significant or persistent symptoms. Nonspecific antidiarrheal agents typically do not address the underlying pathophysiology responsible for the diarrhea; their principal utility is to provide symptomatic relief in mild cases of acute diarrhea. Many of these agents act by decreasing intestinal motility and should be avoided as much as possible in acute diarrhoea illnesses caused by invasive organisms. In such cases, these agents may mask the clinical picture, delay clearance of organisms, and increase the risk of systemic invasion by the infectious organisms; they also may induce local complications such as toxic megacolon.
Bulk-Forming and Hydroscopic Agents
Hydrophilic and poorly fermentable colloids or polymers such as carboxymethylcellulose and calcium polycarbophil absorb water and increase stool bulk (calcium polycarbophil absorbs 60 times its weight in water). They usually are used for constipation , but are sometimes useful in mild chronic diarrheas in patients suffering with irritable bowel syndrome.
Mechanism of Action of Bulk-Forming and Hydroscopic Agents
- They may work as gels to modify stool texture and viscosity and to produce a perception of decreased stool fluidity.
- Some of these agents also may bind bacterial toxins and bile salts.
Clays such as kaolin (a hydrated aluminum silicate) and other silicates such as attapulgite (magnesium aluminum disilicate; DIASORB) bind water avidly (attapulgite absorbs eight times its weight in water) and may may bind enterotoxins. However, this effect is not selective and may involve other drugs and nutrients; hence these agents are best avoided within 2 to 3 hours of taking other medications. A mixture of kaolin and pectin (a plant polysaccharide) is a popular over-the-counter remedy (KAOPECTOLIN) and may provide useful symptomatic relief of mild diarrhea.
Bile Acid Sequestrants
Cholestyramine, colestipol, and colesevalam effectively bind bile acids and some bacterial toxins.
Cholestyramine is useful in the treatment of bile salt-induced diarrhea, as in patients with resection of the distal ileum. In these patients, there is partial interruption of the normal enterohepatic circulation of bile salts, resulting in excessive concentrations reaching the colon and stimulating water and electrolyte secretion . In such patients, the use of cholestyramine will aggravate the diarrhea. The drug also has had an historic role in treating mild antibiotic-associated diarrhea and mild colitis due to Clostridium difficile. However, its use in infectious diarrheas generally is discouraged, as it may decrease clearance of the pathogen from the bowel.
Bismuth
Bismuth compounds have been used to treat a variety of gastrointestinal diseases and symptoms for centuries, although their mechanism of action remains poorly understood. PEPTO-BISMOL (bismuth subsalicylate) is an over-the-counter preparation. It is a crystal complex consisting of trivalent bismuth and salicylate suspended in a mixture of magnesium aluminum silicate clay. In the low pH of the stomach, the bismuth subsalicylate reacts with hydrochloric acid to form bismuth oxychloride and salicylic acid. While 99% of the bismuth passes unaltered and unabsorbed into the feces, the salicylate is absorbed in the stomach and small intestine. Thus, caution should be used in patients taking salicylates for other indications.
Bismuth is thought to have antisecretory, antiinflammatory, and antimicrobial effects. Nausea and abdominal cramps also are relieved by bismuth. Bismuth subsalicylate has been used extensively for the prevention and treatment of traveler’s diarrhea, but it also is effective in other forms of episodic diarrhea and in acute gastroenteritis.
Antimotility and Antisecretory Agents
Examples of these include
- diphenoxylate
- difenoxin
- loper amide.
Opioids
Opioids continue to be widely used in the treatment of diarrhea. They act by several different mechanisms, mediated principally through either µ- or ð-opioid receptors on enteric nerves, epithelial cells, and muscle.
Mechanism of Action of Opioids
These mechanisms include effects on intestinal motility (µ receptors), intestinal secretion (ð receptors), or absorption (µ and ð receptors).
Commonly used antidiarrheals such as diphenoxylate, difenoxin, and loperamide act principally via peripheral µ -opioid receptors and are preferred over opioids that penetrate the CNS.
Loperamide
Loperamide, a piperidine butyramide derivative with µ -receptor activity, is an orally active antidiarrheal agent. The drug is 40 to 50 times more potent than morphine as an antidiarrheal agent and penetrates the CNS poorly.
Mechanism of Action of Loperamide
- It increases small intestinal and mouth-to-cecum transit times.
- Loperamide also increases anal sphincter tone, an effect that may be of therapeutic value in some patients who suffer from anal incontinence.
- In addition, loperamide has antisecretory activity against cholera toxin and some forms of E. coli toxin, presumably by acting on Gi-linked receptors and countering the increase in cellular cyclic AMP generated in response to the toxins.
Because of its effectiveness and safety, loperamide is marketed for over-the-counter distribution and is available in capsule, solution, and chewable forms. It acts quickly after an oral dose, with peak plasma levels achieved within 3 to 5 hours. It has a half-life of about 11 hours and undergoes extensive hepatic metabolism. The usual adult dose is 4 mg initially followed by 2 mg after each subsequent loose stool, up to 16 mg per day. If clinical improvement in acute diarrhea does not occur within 48 hours, loperamide should be discontinued. Recommended maximum daily doses for children are 3 mg for ages 2 to 5 years, 4 mg for ages 6 to 8 years, and 6 mg for ages 8 to 12 years. Loperamide is not recommended for use in children younger than 2 years of age.
Loperamide has been shown to be effective against traveler’s diarrhea, used either alone or in combination with antimicrobial agents (trimethoprim, trimethoprim-sulfamethoxazole, or a fluoroquinolone). Loperamide also has been used as adjunct treatment in almost all forms of chronic diarrheal disease, with few adverse effects. Loperamide lacks significant abuse potential and is more effective in treating diarrhea than diphenoxylate .
Diphenoxylate and Difenoxin
Diphenoxylate and its active metabolite difenoxin (diphenoxylic acid) are piperidine derivatives that are related structurally to meperidine. As antidiarrheal agents, diphenoxylate and difenoxin are somewhat more potent than morphine. Both compounds are extensively absorbed after oral administration, with peak levels achieved within 1 to 2 hours. Diphenoxylate is rapidly deesterified to difenoxin, which is eliminated with a half-life of about 12 hours. Both drugs can produce CNS effects when used in higher doses (40 to 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 g 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 to 4 hours. 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.).
Other opioids used for diarrhea include codeine (in doses of 30 mg given three or four times daily) and opium-containing compounds.
α2 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 is an octapeptide analog of somatostatin that is effective in inhibiting the severe secretory diarrhea brought about by hormone-secreting tumors of the pancreas and the gastrointestinal tract. Its mechanism of action appears to involve inhibition of hormone secretion, including serotonin and various other GI peptides (e.g., gastrin, vasoactive intestinal polypeptide, insulin, secretin, etc.). Octreotide has been used, 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 half-life of 1 to 2 hours and is administered either subcutaneously or intravenously as a bolus dose. Standard initial therapy with octreotide is 50 to 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 long-acting 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 vasoactive intestinal peptide-secreting tumors, as well as in the treatment of acromegaly
Other Agents
Chloride channel blockers are effective antisecretory agents in vitro but are too toxic for human use and have not proven to be effective antidiarrheal agents in vivo. Calmodulin inhibitors, which include chlorpromazine, also are antisecretory. Zaldaride maleate, a new drug in this class, may be effective in traveler’s diarrhea by reducing secretion without affecting intestinal motility.
Conclusion
In diarrhoea treatment, an attempt should be made to find the underlying cause and target it specifically. If no such cause is found, chronic diarrhea can be treated empirically, with the simplest approach being bulk-forming and hygroscopic agents, followed by opioids such as loperamide or diphenoxylate/difenoxin.