A 22-year-old man presents for the evaluation of abdominal pain and diarrhea.
Diarrhea with Abdominal Pain
A 22-year-old man presents for the evaluation of abdominal pain and diarrhea. He states that for about a month he has had progressively worsening cramping pains. He has had watery diarrhea and, from time to time, has noted blood mixed in with his stool. He has lost about 5 pounds. He has tried over-thecounter antidiarrheal medications without relief. He is on no medication regularly and has no significant medical history.
Examination of his abdomen reveals it to be distended and to have hyperactive bowel sounds. It is diffusely tender with no palpable masses. Rectal examination is very painful and reveals heme positive watery stool. A blood count shows that he has iron deficiency anemia and an erythrocyte sedimentation rate that is markedly elevated. An office sigmoidoscopy reveals changes consistent with ulcerative colitis. You start him on a short course of corticosteroids and plan to place him on longterm sulfasalazine.
- What is the mechanism of action of sulfasalazine?
- Sulfasalazine cannot be used by persons allergic to which class of antibiotics?
Agents for Lower Gastrointestinal (GI) Disorders
Summary: A 22-year-old man with ulcerative colitis is started on a short course of corticosteroids and long-term sulfasalazine.
Mechanism of action of sulfasalazine: 5-aminosalicylic acid (5-ASA) component of sulfasalazine inhibits leukotriene and prostaglandin production in the colon.
Sulfasalazine cannot be used by persons allergic to: Sulfonamides.
Sulfasalazine is used to achieve and maintain remission in persons with inflammatory bowel disease (IBD: ulcerative colitis and Crohn disease). It is composed of two constituents—5-ASA bound by an AZO bond (N=N) to sulfapyridine. The AZO bond limits the gastrointestinal (GI) absorption of the inactive, parent compound. However, in the terminal ileum and colon, bacteria break down sulfasalazine into its two components. 5-ASA is the active antiinflammatory component. Its mechanism of action, while not entirely known, is thought to involve inhibition of the production of inflammatory leukotrienes and prostaglandins in the colon. Its activity is terminated by hepatic acetylation. Sulfapyridine, which is also acetylated, does not appear to play an active role in the reduction of inflammation in the colon.
Sulfapyridine mediates the allergic cross reaction with sulfonamide drugs. 5-ASA can also be administered as mesalamine, balsalazide, and olsalazine, which do not have a sulfa component. Sulfasalazine, balsalazide, and olsalazine are administered orally. Mesalamine has oral, suppository, and enema formulations. The many adverse effects of sulfasalazine, attributable primarily to the systemic actions of sulfapyridine, which for many patients is not tolerated, and which is more common in slow acetylators than fast acetylators, includes severe GI discomfort with nausea, headache, myalgia, bone marrow suppression, possible oligospermia that is reversible, and a hypersensitivity with numerous attendant serious sequelae.
Pharmacology of Agents That Act on the Lower GI Tract
Discussion of Class
- List drugs used as antidiarrheal agents and describe their mechanisms of action, therapeutic uses, and adverse effects.
- List drugs used as laxatives and describe their mechanisms of action and adverse effects.
- List drugs used to treat irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).
The agents used for acute treatment of diarrhea of mild to moderate severity may also be used for control of chronic diarrhea resulting from inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) .
Octreotide is used primarily to treat diarrhea stemming from gastrointestinal tumors, AIDS, short-bowel syndrome, vagotomy, and dumping syndrome. At low doses (50 mcg subcutaneously), octreotide is used to stimulate intestinal motility in patients with conditions that lead to intestinal obstruction or bacterial overgrowth.
Prolonged use of high doses of diphenoxylate can result in opioid dependence.
When administered concomitantly (within 2 hours of one another) kaolins and pectins may bind other drugs in the gastrointestinal tract and reduce their absorption.
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 polyethylene glycol [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.
Kaolin is a natural 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 gastrointestinal tract.
The opioids loperamide and diphenoxylate inhibit the 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 gastrointestinal tract.
Cholestyramine and colestipol bind excess diarrhea-causing bile salts that may accumulate in Crohn 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 mcg) or decreased (100–250 mcg) 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 GI 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.
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.
Polyethylene glycol is administered with an isotonic balanced salt solution to prevent the development of intravascular fluid or electrolyte imbalance.
Commercial preparations of kaolin and pectin are not absorbed from the gastrointestinal 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 somatostatin, 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.