Chapter 42: Drugs That Affect the GI Tract

The organization of these drugs is based on the organization of the GI tract. There are drugs that are used in treating ulcers in the stomach and duodenum. There are also drugs that affect motility in the upper GI tract. Then, moving down to the large intestine, we can divide the agents into those that enhance motility and those that reduce motility. Finally, there are agents that specifically target diseases of the lower GI tract.

Orlistat binds to pancreatic and gastric lipase and inactivates the enzyme. This reduces the absorption of dietary fat by about 30%. Adverse effects include flatulence, oily spotting, and fecal urgency.

Duodenal and gastric ulcers are often caused by the bacterium Helicobacter pylori. The treatment objective is eradication of H. pylori with a combination of antibiotics and H₂ blockers. Bismuth (PEPTO-BISMOL) appears to be bactericidal to H. pylori.

These drugs are superior to H₂ antagonists in the suppression of acid and in the healing of peptic ulcers.

These drugs are easily recognizable by the “-tidine” ending. These drugs are used for the short-term treatment of gastroesophageal reflux and peptic ulcer disease. Cimetidine binds to cytochrome P450. Therefore, adverse drug interactions with drugs transformed via the cytochrome P450 system are common with cimetidine.

Antacids can decrease the absorption of other drugs because they alter the stomach and duodenal pH. They can also bind to drugs and block their absorption. This is particularly true for the aluminum salts. Antacids also have systemic effects. Magnesium salts can cause hypermagnesemia and aluminum salts can cause hypophosphatemia.

Sucralfate is only minimally absorbed. Constipation is the main side effect.

Metoclopramide has both peripheral and central effects. Centrally, it is a dopamine antagonist and has produced extrapyramidal side effects. Peripherally, it stimulates release of acetylcholine. Cisapride has been removed from the market in the United States due to cardiac arrhythmias.

Diarrhea is most often caused by infection, toxins, or drugs. Bacterial or parasitic diarrhea should be treated with the appropriate agent for the infection. Drug-induced diarrhea should be treated by discontinuation of the drug, if possible. An example of targeted therapy for diarrhea is the use of octreotide (synthetic somatostatin) for the diarrhea associated with vasoactive intestinal peptide secreting tumors and metastatic carcinoid tumors (they secrete serotonin).

Opiates that are used to treat diarrhea include DIPHENOXYLATE and LOPERAMIDE. Eluxadoline is a μ receptor agonist and δ receptor antagonist that is approved for use in irritable bowel syndrome with diarrhea. These opiates should not be used for an infectious process. Antagonists of the 5-HT₃ receptor have been shown to also decrease transit in the GI tract. Alosetron and ondansetron have been used for this indication. There are also absorbent powders such as KAOPECTATE that are used in the treatment of diarrhea. Bismuth subsalicylate (PEPTO-BISMOL) may coat irritated mucosal surfaces.

Drugs used to treat constipation can be divided into two groups: the bulk-forming agents and the stimulants and cathartics. These drugs are generally taken orally. Some can be administered by insertion into the rectum.

Irritable bowel syndrome can be associated with either or both constipation and diarrhea. Spasms of the smooth muscle can cause considerable pain and are treated with antispasmodics, such as hyoscyamine or dicyclomine. These drugs have direct actions to cause muscle relaxation and are anticholinergic.

You probably recognize these more by their trade names of METAMUCIL (psyllium), DULCOLAX (bisacodyl), and EX LAX (phenolphthalein). It helps to remember which are bulk-formers and which are stimulants.

There are a couple of others that you may be asked about. Saline salts of magnesium and sodium (MILK OF MAGNESIA) draw water into the colon. Docusate (COLACE) improves penetration of water and fat into feces.

Lubiprostone, a prostaglandin E1 analogue, is approved for the treatment of chronic constipation and irritable bowel syndrome with constipation. It activates chloride channels in the epithelium of the GI tract, stimulating intestinal fluid secretion.

Also approved for irritable bowel syndrome with constipation is linaclotide, a peptide that activates guanylate cyclase receptors on the epithelium of the intestine. This results in increase secretions into the lumen and accelerated transit.

INFLAMMATORY BOWEL DISEASE

Inflammatory bowel disease is generally divided into ulcerative colitis and Crohn’s disease. For both of these diseases consideration needs to be given to induction of remission and maintenance of remission. Sometimes the same drugs are used for both, but not always. These details are secondary to getting down the main drugs classes used for these conditions.

In the table above, see if you can list at least one drug for each category.

Primary therapy utilizes steroids and 5-aminosalicyclate (5-ASA), also called mesalamine, to control the inflammatory process. 5-ASA probably inhibits leukotriene production and has antiprostaglandin and antioxidant activity. Sulfasalazine, balsalazide and olsalazine (prodrugs for mesalamine), and mesalamine itself are used in mild to moderate ulcerative colitis and for maintenance of remission in ulcerative colitis.

Immunomodulating agents are also used in inflammatory bowel disease—including azathioprine, mercaptopurine, methotrexate, and cyclosporine (Chapters 35 and 44). In addition, antibodies and antibody fragments that bind to tumor necrosis factor alpha (TNF-α) block the inflammatory cascade and can be used in inflammatory bowel disease. Infliximab and adalimumab are monoclonal antibodies that bind to and inhibit TNF-α. Certolizumab pegol is an antibody fragment that is also used. These TNF-α inhibitors are generally reserved for disease refractory to more conventional therapy. Natalizumab and vedolizumab are monoclonal antibodies that are used in Crohn’s disease. They reduce intestinal inflammation by binding α-4 integrin, a molecule that mediates adhesion of leukocytes to endothelial receptors.