Case: agents for lower GI disorders. Class

The agents used for acute treatment of diarrhea of mild-to-moderate severity (Table: Antidiarrheal agents) may also be used for control of chronic diarrhea resulting from IBD and IBS (Table: Drugs used to treat bowel disorders). When constipation is predominant, laxatives,particularly osmotic laxatives (e.g., magnesium oxide), are used as stool softeners (Table: Antidiarrheal agents).

Table: Antidiarrheal agents

Selected Antidiarrheal Agents	Selected Laxatives
Opioid agonistsLoperamide Diphenoxylate	Bulk-forming laxativesPsyllium preparations Methylcellulose Calcium polycarbophil
Kaolin	Osmotic laxativesMagnesium citrate Sodium phosphate Magnesium sulfate Sorbitol Lactulose PEG
Pectin	Stool softenersDocusate Glycerin Mineral oil
Methylcellulose resinsCholestyramine Colestipol	Stimulant laxatives(infrequently used) Aloe, senna, cascara, castor oil
Bismuth subsalicylate

PEG = polyethylene glycol.

Octreotide, an analog of somatostatin, is used primarily to treat diarrhea stemming from GI tumors, AIDS, short-bowel syndrome, vagotomy, and dumping syndrome. At low doses (50 meg subcutaneously), octreotide is used to stimulate intestinal motility in patients with conditions that lead to intestinal obstruction or bacterial overgrowth.

Table: Drugs used to treat bowel disorders

Drugs Used to Treat IBS	Drugs Used to Treat IBD
*AlosetronTegaserod	AminosalicylatesSulfasalazine Balsalazide Olsalazine Mesalamine
Antispasmodic agentsCalcium channel antagonists, anticholinergic agents, opioid receptor antagonists	Glucocorticoids
Tricyclic antidepressantsNortryptiline (e.g.)	Purine analogsAzathioprine 6 -Mercaptopurine
	Methotrexate
	Anti-TNF-α agentsInfliximab

* Requires physician certification and consent protocol.

IBS = irritable bowel syndrome; IBD = inflammatory bowel disease.

Opioids

Prolonged use of high doses of diphenoxylate can result in opioid dependence.

Kaolin-Pectin

When administered concomitantly (within 2 hours of one another) kaolins and pectins may bind other drugs in the GI tract and reduce their absorption.

Methylcellulose Resins

Cholestyramine and colestipol may cause bloating and constipation and in some patients may result in insufficient absorption of fat. Like kaolin-pectin, the use of octreotide may result in constipation and abdominal pain. The formation of gallstones resulting from reduced gallbladder contractility, and the development of hyperglycemia, and sometime hypoglycemia, as a consequence of an imbalance in the secretions of insulin, glucagons, and growth hormone may also occur with octreotide therapy. Reduced pancreatic secretions may result in steatorrhea and deficiency of fat-soluble vitamins.

Bulk-Forming and Osmotic Laxatives

Bulk-forming and osmotic laxatives (except PEG) can cause flatulence and bloating. Osmotic laxatives can result in electrolyte imbalance and should be used cautiously in patients with renal insufficiency or cardiac dysfunction. PEG is used to cleanse the colon prior to endoscopy. If aspirated, mineral oil can cause severe lipid pneumonia and when used chronically can result in decreased fat-soluble vitamin absorption.

Structure

Kaolin is a naturally occurring hydrated magnesium aluminum silicate, whereas pectin is derived from apples.

Octreotide is a more stable, biologically active octapeptide analog of the 14-amino acid regulatory peptide, somatostatin.

PEG is an osmotically active sugar.

Mechanism of Action

Kaolin and pectin absorb fluids as well as bacteria and other toxic agents in the GI tract.

The opioids, loperamide, and diphenoxylate inhibit the release of acetyl-choline from cholinergic nerves in the submucosa and myenteric complex to disrupt coordinated colonic motility and to increase water absorption and transit time through the GI tract.

Cholestyramine and colestipol bind excess diarrhea-causing bile salts that may accumulate in Crohn’s disease or from resection of the terminal ileum where bile salts are normally absorbed.

Octreotide, like somatostatin, inhibits the release of numerous GI hormones (e.g., gastrin, cholecystokinin, serotonin) that results in decreased intestinal fluid secretion and, depending on the subcutaneous dose, increased (50 meg) or decreased (100-250 meg) motility among many other effects, including reduced pancreatic secretions.

Bulk-forming laxatives, which are not absorbed from the GI tract, absorb water to form a gel or increase the fluidity of the stools that distends the colon and induces peristalsis. Osmotic laxatives, which are also not absorbed from the gastrointestinal tract, increase the fluidity of stools. Stool softeners increase the penetration of water and lipids into compacted fecal material (docusate, glycerin) or coat it (mineral oil) to prevent the loss of water.

Administration

Loperamide, administered orally, is a nonprescription opioid agonist. Diphenoxylate is administered orally in combination with low doses of atropine (which also may contribute to the antidiarrheal activity of the preparation) to preclude its self-administration as a drug of abuse.

Octreotide can be administered intravenously or subcutaneously and in a subcutaneous depot formulation.

All laxatives are administered orally except glycerin, which is administered rectally as a suppository.

PEG is administered with an isotonic balanced salt solution to prevent the development of intravascular fluid or electrolyte imbalance.

Pharmacokinetics

Commercial preparations of kaolin and pectin are not absorbed from the GI tract.

Loperamide does not cross the blood-brain barrier and therefore has no analgesic activity or, importantly, potential for abuse that limits the use of other opioids as antidiarrheal agents.

Diphenoxylate, although very insoluble, does penetrate the central nervous system (CNS), and therefore its continuous use can result in opioid dependence.

Octreotide has a serum half-life of 90 minutes, compared with somato-statin, which has a serum half-life of approximately 3 minutes. Its duration of action can be extended up to 12 hours by subcutaneous administration and up to a month by using a depot formulation.

Sorbitol and lactulose are metabolized by colonic bacteria.

Questions

[1] Which of the following drugs crosses the blood-brain barrier?

A. Diphenoxylate

B. Kaolin

C. Loperamide

D. Methylcellulose

[2] Which of the following drugs inhibits the release of acetylcholine from cholinergic nerves in the submucosa and myenteric complex?

A. Cholestyramine

B. Docusate

C. Loperamide

D. Pectin

[3] Which of the following drugs shows an allergic cross-reaction with an antibiotic?

A. Diphenoxylate

B. Octreotide

C. PsyIlium

D. Sulfasalazine

Answers

[1] A. Diphenoxylate can cross the blood-brain barrier and cause dependence. Methylcellulose and kaolin are not absorbed from the GI tract. Loperamide does not cross the blood-brain barrier.

[2] C. The opioid loperamide inhibits release of acetylcholine from cholinergic nerves in the submucosa and myenteric complex to disrupt coordinated colonic motility and to increase water absorption and transit time through the GI tract. Pectin absorbs fluids in the gastrointestinal tract. Stool softeners like docusate increase the penetration of water and lipids into compacted fecal material.

[3] D. Sulfasalazine is composed of 5-AS A and sulfapyridine. Sulfapyridine, which does not appear to play an active role in the reduction of inflammation in the colon, mediates an allergic cross-reaction with sulfonamide drugs.

Pharmacology pearls

Antidiarrheal agents should not be used to treat patients experiencing bloody stools or high fever because of the increased risk of aggravating the underlying condition.

Cholestyramine and colestipol bind excess diarrhea-causing bile salts.

Many laxatives are commonly overused by the lay public.