Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 59. Drugs Used in Gastrointestinal Disorders

High-Yield Terms to Learn

Acid-peptic disease A group of disorders involving erosion or ulceration of the mucosal lining of the gastrointestinal tract; includes GERD, gastric and duodenal ulcers, nonulcer dyspepsia, and stress-related gastritis AntiemeticA drug that reduces nausea and vomiting Gastroesophageal reflux disease (GERD) Esophageal irritation or inflammation due to reflux of stomach acid; also known as heartburn Gastroparesis Paralysis of the muscles of the stomach and possibly other parts of the gastrointestinal tract due to damage to gastrointestinal nerves or muscle; common in advanced diabetes and advanced Parkinson disease Inflammatory bowel disease (IBD) Inflammatory disorder involving irritation and ulceration of the colon and rectum (ulcerative colitis) or the colon plus more proximal parts of the gastrointestinal tract (Crohn's disease) Irritable bowel syndrome (IBS) Disease of unknown origin characterized by episodes of abdominal discomfort and abnormal bowel function (diarrhea, constipation, or both) Prokinetic A drug that promotes gastrointestinal motility Proton pump The parietal cell H+/K+ ATPase that uses the energy of ATP to secrete protons into the stomach (Figure 59-1); final common target of drugs that suppress acid secretion

Drugs Used in Gastrointestinal Disorders: Introduction

The gastrointestinal tract serves many important functions: digestive, excretory, endocrine, exocrine, and so on. These functions are the targets of several important classes of drugs. Some of these drugs have been discussed previously. This chapter mentions them and discusses in more detail others that do not fall into the classes of agents described previously.

Drugs Used in Acid-Peptic Disease

Ulceration and erosion of the lining of the upper portion of the gastrointestinal tract are common problems that manifest as gastroesophageal reflux disease (GERD), gastric and duodenal peptic ulcers, and stress-related mucosal injury. Drugs used in acid-peptic disease reduce intragastric acidity by manipulating systems controlling hydrogen acid secretion (Figure 59-1), promote mucosal defense or, in the case of peptic ulcers, eradicate the bacterium Helicobacter pylori, which is detectable in over 80% of patients with duodenal ulcers.

FIGURE 59-1

Schematic model of physiologic control of hydrogen ion (acid) secretion by the gastric parietal cells, which are stimulated by gastrin (acting on gastrin/CCK-B receptors), acetylcholine (ACh; M3 receptor), and histamine (H2 receptor). Acid is secreted across the parietal cell canalicular membrane by the H+/K+ ATPase proton pump into the gastric lumen. The gastrin that is secreted by antral G cells in response to intraluminal dietary peptides acts directly on parietal cells and also stimulates release of histamine from enterochromaffin-like (ECL) cells. The vagus nerve stimulates postganglionic neurons of the enteric nervous system to release acetylcholine ACh, which acts on parietal and ECL cells. In the antrum, release of gastrin-releasing peptide (GRP) from postganglionic neurons directly increases gastrin release, whereas release of ACh indirectly increases gastrin secretion by inhibiting release of somatostatin from antral D cells. The increase in intraluminal H+ concentration causes D cells to release somatostatin and thereby inhibit gastrin release from G cells. CCK, cholecystokinin; R, receptor.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 62-1.)

Antacids

Antacids are weak bases that neutralize stomach acid by reacting with protons in the lumen of the gut and may also stimulate the protective functions of the gastric mucosa. When used regularly in the large doses needed to significantly raise the stomach pH, antacids reduce the recurrence rate of peptic ulcers.

The antacids differ mainly in their absorption and effects on stool consistency. Popular antacids include magnesium hydroxide (Mg[OH]2) and aluminum hydroxide (Al[OH]3). Neither of these weak bases is significantly absorbed from the bowel. Magnesium hydroxide has a strong laxative effect, whereas aluminum hydroxide has a constipating action. These drugs are available as single-ingredient products and as combined preparations. Calcium carbonate and sodium bicarbonate are also weak bases, but they differ from aluminum and magnesium hydroxides in being absorbed from the gut. Because of their systemic effects, calcium and bicarbonate salts are less popular as antacids.

H2-Receptor Antagonists

Cimetidine and other H2 antagonists (ranitidine, famotidine, and nizatidine) inhibit stomach acid production. They are effective in the treatment of GERD, peptic ulcer disease, and nonulcer dyspepsia and in the prevention of stress-related gastritis in seriously ill patients. Although they are still used widely, their clinical use is being supplanted by the more effective and equally safe proton pump inhibitors. The H2 antagonists are described in detail in Chapter 16.

Proton Pump Inhibitors

Omeprazole and other proton pump inhibitors (esomeprazole, lansoprazole, pantoprazole, and rabeprazole) are lipophilic weak bases that diffuse into the parietal cell canaliculi, where they become protonated and concentrated more than 1000-fold. There they undergo conversion to compounds that irreversibly inactivate the parietal cell H+/K+ ATPase, the transporter that is primarily responsible for producing stomach acid. Oral formulations of these drugs are enteric coated to prevent acid inactivation in the stomach. After absorption in the intestine, they are rapidly metabolized in the liver, with half-lives of 1-2 h. However, their durations of action are approximately 24 h, and they may require 3-4 d of treatment to achieve their full effectiveness.

Proton pump inhibitors are more effective than H2 antagonists for GERD and peptic ulcer and equally effective in the treatment of nonulcer dyspepsia and the prevention of stress-related mucosal bleeding. They are also useful in the treatment of Zollinger-Ellison syndrome. Adverse effects of proton pump inhibitors occur infrequently and include diarrhea, abdominal pain, and headache. Chronic treatment with proton pump inhibitors may result in hypergastrinemia. However, there is no documentation that the use of these drugs increases the incidence of carcinoid or colon cancer. Proton pump inhibitors may decrease the oral bioavailability of vitamin B12 and certain drugs that require acidity for their gastrointestinal absorption (eg, digoxin, ketoconazole). Patients taking proton pump inhibitors may have a small increase in the risk of respiratory and enteric infections.

Sucralfate

An aluminum sucrose sulfate, sucralfate is a small, poorly soluble molecule that polymerizes in the acid environment of the stomach. The polymer binds to injured tissue and forms a protective coating over ulcer beds. Sucralfate accelerates the healing of peptic ulcers and reduces the recurrence rate. Unfortunately, sucralfate must be taken 4 times daily. Sucralfate is too insoluble to have significant systemic effects when taken by the oral route; toxicity is very low.

Misoprostol

An analog of PGE1 , misoprostol increases mucosal protection and inhibits acid secretion. It is effective in reducing the risk of ulcers in users of nonsteroidal anti-inflammatory drugs (NSAIDs) but is not widely used because of the need for multiple daily dosing and poorly tolerated adverse effects (gastrointestinal upset and diarrhea). Misoprostol is discussed in detail in Chapter 18.

Colloidal Bismuth

Bismuth has multiple actions, including formation of a protective coating on ulcerated tissue, stimulation of mucosal protective mechanisms, direct antimicrobial effects, and sequestration of enterotoxins. Bismuth subsalicylate, a nonprescription formulation of bismuth and salicylate, reduces stool frequency and liquidity in infectious diarrhea. Bismuth causes black stools.

Antibiotics

Chronic infection with H pylori is present in most patients with recurrent non-NSAID-induced peptic ulcers. Eradication of this organism greatly reduces the rate of recurrence of ulcer in these patients. One regimen of choice consists of a proton pump inhibitor plus a course of clarithromycin and amoxicillin (or metronidazole in patients with penicillin allergy).

Drugs That Promote Upper Gastrointestinal Motility

Prokinetic drugs that stimulate upper gastrointestinal motility are helpful for gastroparesis and for postsurgical gastric emptying delay. Their ability to increase lower esophageal sphincter pressures also makes them useful for some patients with GERD. In the past, cholinomimetic agonists such as bethanechol were used for GERD and gastroparesis, but the availability of less toxic agents has supplanted their use. The acetylcholinesterase inhibitor neostigmine is still used for the treatment of hospitalized patients with acute large bowel distention. The cholinomimetics are discussed in Chapter 7.

In the enteric nervous system, dopamine serves an inhibitory function by inhibiting cholinergic stimulation of smooth muscle contraction. Metoclopramide and domperidone are D2 dopamine receptor antagonists that promote gastrointestinal motility. The D2 receptor-blocking action of these drugs in the area postrema is also of value in preventing emesis after surgical anesthesia and emesis induced by cancer chemotherapeutic drugs. When used chronically, metoclopramide can cause symptoms of parkinsonism, other extrapyramidal effects, and hyperprolactinemia. Because it does not cross the blood-brain barrier, domperidone is less likely to cause CNS toxicity.

The antibiotic erythromycin (Chapter 44) promotes motility by stimulating motilin receptors. It may have benefit in some patients with gastroparesis.

Laxatives

Laxatives increase the probability of a bowel movement by several mechanisms: an irritant or stimulant action on the bowel wall; a bulk-forming action on the stool that evokes reflex contraction of the bowel; a softening action on hard or impacted stool; and a lubricating action that eases passage of stool through the rectum. Examples of drugs that act by these mechanisms are listed in Table 59-1.

TABLE 59-1 The major laxative mechanisms and some representative laxative drugs.

Mechanism Examples Bulk-forming Psyllium, methylcellulose, polycarbophil Stool-softening Docusate, glycerin, mineral oil Osmotic Magnesium oxide, sorbitol, lactulose, magnesium citrate, sodium phosphate, polyethylene glycol Stimulant Aloe, senna, cascara, castor oil, bisacodyl Chloride channel activator Lubiprostone Opioid receptor antagonists Methylnaltrexone, alvimopan 5-HT 4 receptor agonist

Tegaserod

Antidiarrheal Agents

The most effective antidiarrheal drugs are the opioids and derivatives of opioids that have been selected for maximal antidiarrheal and minimal CNS effect. Of the latter group, the most important are diphenoxylate and loperamide, meperidine analogs with very weak analgesic effects. Diphenoxylate is formulated with antimuscarinic alkaloids (eg, atropine) to reduce the likelihood of abuse; loperamide is formulated alone. Kaolin , a naturally occurring hydrated magnesium aluminum silicate, is combined with pectin , an indigestible carbohydrate derived from apples in a popular nonprescription preparation that absorbs bacterial toxins and fluid, resulting in decreased stool liquidity. They can cause constipation and interfere with absorption of other drugs.

Drugs Used for Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is associated with relapsing episodes of abdominal discomfort (pain, bloating, distention, or cramps) plus diarrhea or constipation (or both). The pharmacologic strategy is tailored to patients' symptoms and includes antidiarrheal agents and laxatives, and for the treatment of abdominal pain, low doses of tricyclic antidepressants (Chapter 30). The anticholinergic drugs dicyclomine and hyoscyamine are used as antispasmodics to relieve abdominal pain; however, their efficacy has not been convincingly demonstrated. Alosetron , a potent 5-HT 3 antagonist, is approved for treatment of women with severe IBS with diarrhea. Alosetron can cause constipation, including rare complications of severe constipation that have required hospitalization or surgery, and rare cases of ischemic colitis. For this reason, its use is restricted. It is not known whether the less potent 5-HT3 receptor antagonists that are used as antiemetics (such as ondansetron) have efficacy in IBS.

Drugs with Antiemetic Actions

A variety of drugs are valuable in the prevention and treatment of vomiting, especially cancer chemotherapy-induced vomiting. In addition to metoclopramide and other D2 dopamine receptor antagonists,useful antiemetics are drugs with H 1histamine-blocking activity (Chapter 16), including diphenhydramine and several phenothiazines (Chapter 29); antimuscarinic drugs such as scopolamine (Chapter 8); the corticosteroid dexamethasone (Chapter 39); and the cannabinoid receptor agonists dronabinol and nabilone (Chapter 32). The 5-HT 3 antagonists (Chapter 16) ondansetron, granisetron, dolasetron,and palonosetron are particularly useful in preventing nausea and vomiting after general anesthesia and in patients receiving cancer chemotherapy. Aprepitant a newer antiemetic is an antagonist of the neurokinin 1 (NK1) receptor, a receptor in the area postrema of the CNS that is activated by substance P and other tachykinins (see Chapter 17). Aprepitant is approved for use in combination with other antiemetics for prevention of the nausea and vomiting associated with highly emetogenic chemotherapeutic regimens. Aprepitant can cause fatigue, dizziness, and diarrhea. As a substrate and an inhibitor of CYP3A4, aprepitant participates in many drug interactions.

Drugs Used in Inflammatory Bowel Disease (IBD)

Aminosalicylates

Drugs containing 5-aminosalicylic acid ( 5-ASA ) are used as topical therapy for IBD. The precise mechanism of 5-ASA action is uncertain but may involve inhibiting the synthesis of prostaglandins and inflammatory leukotrienes, and interfering with the production of inflammatory cytokines. 5-ASA, known generically as mesalamine, is readily absorbed from the small intestine whereas absorption from the colon is extremely low. Proprietary formulations of 5-ASA (Pentasa, Asacol, Lialda) deliver 5-ASA to different segments of the small and large intestine (Figure 59-2). Balsalazide, olsalazine, and sulfasalazine contain 5-ASA bound by an azo (N=N) bond to an inert compound, another 5-ASA molecule, or sulfapyridine. The azo structure is poorly absorbed in the small intestine. Sulfasalazine (a combination of 5-ASA and sulfapyridine) has a higher incidence of adverse effects that the other 5-ASA drugs, due to the systemic absorption of the sulfapyridine moiety. These effects are dose related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, malaise, and severe hypersensitivity reactions. Other aminosalicylates, which do not contain sulfapyridine, are well tolerated.

FIGURE 59-2

Sites of 5-aminosalicyclic acid (5-ASA) release from different formulations in the small and large intestines.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 62-7.)

Other Agents

Other drugs used in the treatment of ulcerative colitis and Crohn's disease (Figure 59-3) include antibiotics, glucocorticoids (Chapters 39 and 55), immunosuppressive antimetabolites (eg, azathioprine, 6-mercaptopurine, methotrexate; Chapters 54 and 55), anti-tumor necrosis factor [TNF] drugs (eg, infliximab, Chapters 36 and 55). Natalizumab is a humanized monoclonal antibody that blocks integrins on circulating leukocytes. Because of a possible associate of natalizumab with multifocal leukoencephalopathy, it is carefully restricted to patients with severe refractory Crohn's disease.

FIGURE 59-3

Therapeutic pyramid approach to inflammatory bowel disease. Treatment choice is predicted on both the severity of the illness and responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. TNF, tumor necrosis factor.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 62-9.)

Pancreatic Enzyme Replacements

Steatorrhea, a condition of decreased fat absorption together with an increase in stool fat excretion, results from inadequate pancreatic secretion of lipase. The abnormality of fat absorption can be significantly relieved by oral administration of pancreatic lipase ( pancrelipase or pancreatin ) obtained from pigs. Pancreatic lipase is inactivated at a pH lower than 4.0; the enzyme should be taken as enteric-coated capsules unless the pH is raised with antacids or drugs that reduce acid secretion.

Drugs That Inhibit the Formation of Gallstones

The formation of cholesterol gallstones can be inhibited by the bile acid derivative ursodiol, which decreases the cholesterol content of bile by decreasing hepatic cholesterol secretion and other effects on hepatocyte canalicular membranes. Toxicity due to the drug is uncommon.

Skill Keeper: 5-HT Agonists and Antagonists

(See Chapters 16 and 30)

List the various 5-HT receptor agonists and antagonists in current use. Describe their clinical applications. The Skill Keeper Answer appears at the end of the chapter.

Skill Keeper Answer: 5-HT Agonists & Antagonists

(See Chapters 16 and 30)

The only serotonin agonists in common use are the 5-HT1D-selective agonists such as sumatriptan and its congeners (see Chapter 16) that are used in migraine. Ergot alkaloids are partial agonists at several 5-HT receptors and are also used in migraine and other conditions. Several valuable antidepressants are inhibitors of the serotonin reuptake pump in neurons (see Chapter 30). Serotonin antagonists include cyproheptadine (also an H1 blocker), phenoxybenzamine (also an  blocker), and several of the atypical antipsychotic drugs (eg, olanzapine, aripiprazole; see Chapter 29), which have high affinity for HT2A receptors. Cyproheptadine is used for pruritus and sometimes for carcinoid tumor. Phenoxybenzamine is used for carcinoid tumor as well as for pheochromocytoma. 5-HT3 receptors are blocked by ondansetron and its congeners. These drugs are extremely useful in preventing postoperative and cancer chemotherapy-induced nausea and vomiting.

Checklist

When you complete this chapter, you should be able to:

 Identify 5 different groups of drugs used in peptic ulcer disease.

 Describe the mechanism of action of omeprazole and related drugs.

List 7 different drugs used in the prevention of chemotherapy- or radiation-induced emesis and identify the receptors with which they interact.

 Describe the mechanism of action, clinical uses, and adverse effects of metoclopramide.

 Identify 2 drugs commonly used as antidiarrheal agents and 4 drugs with different mechanisms that are used as laxatives.

 Identify drugs used in the management of inflammatory bowel disease and irritable bowel syndrome.

Drug Summary Table: Gastrointestinal Drugs

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Drugs used in acid-peptic diseases Proton pump inhibitors (eg, omeprazole) Irreversible blockade of H+/ K+ ATPase in active gastric parietal; long-lasting reduction of stimulated and nocturnal acid secretion

Peptic ulcer, GERD, erosive gastritis Half-lives much shorter than duration of action Low toxicity; reduction of stomach acid may reduce absorption of some drugs and increase that of others Other proton pump inhibitors: Esomeprazole, lansoprazole, pantoprazole, rabeprazole H2-receptor blockers: Cimetidine, famotidine, nizatidine, ranitidine reduce nocturnal acid but less effective against stimulated secretion; very safe, available over the counter (OTC). Cimetidine, but not other H2 blockers, is a weak antiandrogenic agent and a potent CYP enzyme inhibitor Sucralfate: Polymerizes at site of tissue damage and protects against further damage; very insoluble with no systemic effects; must be given 4 times daily Antacids: Popular OTC medication for symptomatic relief of heartburn; not as useful as proton pump inhibitors and H2 blockers in peptic diseases Prokinetic agents Metoclopramide D2 receptor blocker; increases gastric emptying and intestinal motility

Gastric paresis (eg, in diabetes); antiemetic Oral and parenteral formulations Parkinsonian symptoms due to block of CNS D2 receptors

Domperidone: Like metoclopramide but less CNS effect; not available in United States Cholinomimetics: Neostigmine used for colonic pseudo-obstruction in hospitalized patients Macrolides: Erythromycin useful in diabetic gastroparesis but tolerance develops Drugs for irritable bowel syndrome (IBS) Alosetron 5-HT3 antagonist of high potency and duration of binding; reduces smooth muscle activity in gastrointestinal (GI) tract

Severe diarrhea-predominant IBS in women Oral Rare but serious constipation; ischemic colitis; bowel infarction Anticholinergics: Nonselective action on GI activity; associated with typical antimuscarinic toxicity Chloride channel activator: Lubiprostone is useful in constipation-predominant IBS in women Antiemetics 5-HT3 antagonists (eg, ondansetron)

5-HT3 block in GI and CNS

Prevention of chemotherapy-induced and postoperative nausea and vomiting Oral and parenteral formulations May slow colonic transit Other 5-HT3 antagonist antiemetics: Dolasetron, granisetron, palonosetron; see Chapter 16 Corticosteroids: Mechanism not known but useful in antiemetic IV cocktails; see Chapter 39 Antimuscarinics (eg, scopolamine): Effective in emesis due to motion sickness; not other types; see Chapter 8 Phenothiazines: Act primary through block of D2 and muscarinic receptors; see Chapter 16 Cannabinoids: Dronabinol is available for use in chemotherapy-induced nausea and vomiting, but is associated with CNS marijuana effects (see Chapter 32) Aprepitant: A neurokinin 1 (NK1) antagonist available for use in chemotherapy-induced nausea and vomiting; associated with fatigue, dizziness, diarrhea, and CYP interactions Laxatives Magnesium hydroxide, other nonabsorbable salts and sugars Osmotic agents increase water content of stool Simple constipations; bowel prep for endoscopy (especially PEG solutions) Oral Magnesium may be absorbed and cause toxicity in renal impairment Bulk-forming: Methylcellulose, psyllium, etc; increase volume, stimulate evacuation Stool surfactants: Docusate, mineral oil; lubricate stool, ease passage Stimulants: Senna, cascara; stimulate activity; may cause cramping Chloride channel activator: Lubiprostone, prostanoic acid derivative, stimulates chloride secretion into intestine, increasing fluid content Opioid receptor antagonists: Alvimopan, methylnaltrexone, block intestinal -opioid receptors but do not enter CNS, so analgesia is maintained 5-HT4 agonists: Tegaserod; activates enteric 5-HT4 receptors and increases intestinal motility Antidiarrheal drugs Loperamide Activates -opioid receptors in enteric nervous system and slows motility with negligible CNS effects Nonspecific, noninfectious diarrhea Oral Mild cramping but little or no CNS toxicity Diphenoxylate: Similar to loperamide, but high doses can cause CNS opioid effects and toxicity Colloidal bismuth compounds: Subsalicylate and citrate salts available as over-the-counter products; have some value in travelers' diarrhea due to absorption of toxins Kaolin + pectin: Adsorbent compounds available OTC Drugs for inflammatory bowel disease (IBD) Mesalamine (5-aminosalicylate) Mechanism uncertain; may be inhibition of eicosanoid inflammatory mediators Mild to moderately severe Crohn's disease and ulcerative colitis Various formulations designed to deliver drug to distal ileum and colon Little or no toxicity Azo compounds: Balsalazide, olsalazine, sulfasalazine; colonic bacterial azoreductase enzymes release 5-aminosalicylate in the colon; sulfasalazine can cause sulfonamide toxicity due to absorption of the sulfapyridine moiety Glucocorticoids: see Chapters 30 and 55 Immunosuppressant antimetabolites: see Chapters 54 and 55 Anti-TNF drugs: see Chapters 36, 55 Natalizumab: Antibody that blocks leukocyte integrins; may cause multifocal leukoencephalopathy Pancreatic supplements Pancrelipase Replacement enzymes from animal pancreatic extracts that improve digestion of fat, protein, and carbohydrate Pancreatic insufficiency due to cystic fibrosis, pancreatitis, pancreatectomy Taken with every mean May increase incidence of gout Pancreatin: Similar pancreatic extracts but much lower potency; rarely used Bile acid therapy for gallstones Ursodiol Reduces cholesterol secretion into bile Gallstones in patients refusing or not eligible for surgery Oral Little or no toxicity

GERD, gastrointestinal reflux disease; PEG, pegylated.



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