Chapter 18 Drugs Affecting the Gastrointestinal System

Abbreviations
5-ASA	5-Aminosalicylic acid
5-HT	5-Hydroxytryptamine (serotonin)
ACh	Acetylcholine
AChE	Acetylcholine Sterase
CB	Cannabinoid
CNS	Central nervous system
COX	Cyclooxygenase
CTZ	Chemoreceptor trigger zone
CYP	Cytochrome P450
DA	Dopamine
GERD	Gastroesophageal reflux disease
GI	Gastrointestinal
H. pylori	Helicobacter pylori
IBD	Inflammatory bowel disease
M	Muscarinic
IBS	Irritable bowel syndrome
NK	Neurokinin (substance P)
NSAID	Nonsteroidal antiinflammatory drug
PPIs	Proton pump inhibitors
PUD	Peptic ulcer disease
TNF	Tumor necrosis factor

Therapeutic Overview

The gastrointestinal (GI) tract stores, digests, and absorbs nutrients and eliminates wastes. Regulation of the GI organs is mediated by intrinsic nerves of the enteric nervous system, neural activity in the central nervous system (CNS), and an array of hormones. These processes are summarized in Figure 18-1.

FIGURE 18–1 Regulation and functions of the GI tract, depicting the extrinsic and intrinsic autonomic efferent innervation of the wall of the intestine. The enteric nervous system of the GI tract innervates smooth muscle and mucosa. Efferent and afferent neurons are organized in intramural plexuses; the most prominent plexuses are the myenteric plexus between the longitudinal and circular muscle coats and the submucosal plexus between the circular muscle and the muscularis mucosa.

Pharmacologically treatable GI disorders include:

• Peptic ulcer disease (PUD)

• Gastroesophageal reflux disease (GERD)

• Gastroparesis (delayed gastric emptying)

• Constipation

• Diarrhea

• Irritable bowel syndrome (IBS)

• Inflammatory bowel disease (IBD)

In each case the potential beneficial effects of drugs must be carefully considered against their potential adverse effects.

Peptic ulcers occur primarily in the stomach and duodenum at a site where the mucosal epithelium is exposed to acid and pepsin. There is a constant confrontation between acid-pepsin aggression and mucosal defense in the stomach and upper small bowel. Usually the mucosa can withstand the acid-pepsin attack and remain healthy; that is, a mucosal “barrier” to back-diffusion of acid is maintained. However, an excess of acid production or an intrinsic defect in the barrier functions of the mucosa can cause defense mechanisms to fail and ulcers to form. Although most patients with duodenal ulcers have an increased acid secretion, patients with gastric ulcers often have normal or low rates of acid secretion. The role of pepsin in the development of PUD is not known, despite the name of the disease.

Peptic ulcers are commonly associated with either a gram-negative bacillus, Helicobacter pylori (H. pylori), or chronic use of nonsteroidal antiinflammatory drugs (NSAIDs). Chronic colonization of the gastric and duodenal mucosa with H. pylori is causally associated with PUD.

H. pylori infection produces inflammatory changes in the mucosa, impairs mucosal defense mechanisms (barrier function), and increases acid secretion. Although histamine H₂ receptor antagonists, proton pump inhibitors (PPIs), and sucralfate heal peptic ulcers in H. pylori-positive patients, there is a high rate of ulcer recurrence upon discontinuing drug treatment. Continuous low-dose maintenance therapy reduces the risk of ulcer recurrence but does not cure the disease, because the organism has not been eliminated. Eradication of H. pylori cures the disease and in most patients eliminates the need for continuous antisecretory maintenance therapy.

Nonselective NSAIDs, including aspirin, damage the gastric mucosa by a direct topical effect or by systemic inhibition of endogenous mucosal prostaglandin synthesis. The initial topical injury is caused by the acidic property of the NSAIDs, but inhibition of protective prostaglandins is the primary cause of the ulcer. Nonselective NSAIDs inhibit cyclooxygenase (COX), which is the rate-limiting enzyme in the conversion of arachidonic acid to GI mucosal prostaglandins (see Chapter 15). Two forms of COX exist:

• COX-1, which produces protective prostaglandins that maintain mucosal integrity

• COX-2, which is expressed during inflammation and produces prostaglandins involved with fever and pain

Evidence for a novel COX splice variant (COX-3) has been observed, and it has been proposed that acetaminophen acts selectively on this form, but this remains controversial.

Nonselective NSAIDs inhibit both COX-1 and COX-2 to varying degrees. Selective COX-2 inhibitors such as celecoxib were thought to spare the protective prostaglandins and decrease the incidence of adverse GI effects, but recent evidence has questioned this idea, because COX-2 inhibitors have been observed to increase the risk of adverse cardiac events (see Chapter 36). The concomitant use of a PPI or misoprostol with a nonselective NSAID can reduce the risk of ulcers.

Patients with Zollinger-Ellison syndrome have a hypersecretion of gastric acid caused by a gastrin-secreting tumor (gastrinoma). The excess acid overwhelms the mucosal barrier and results in severe and multiple duodenal ulcers. PPIs are the drugs of choice for treating patients with such hypersecretory disorders.

GERD is most often associated with inappropriate relaxation of the lower esophageal sphincter, which allows the acidic gastric contents to flow into the esophagus. The most common symptom of GERD is indigestion or heartburn, but some patients also develop inflammation, erosions of the esophageal mucosa (esophagitis), and extraesophageal (atypical) manifestations including chronic asthma, cough, and laryngitis. GERD is treated using drugs that decrease gastric acidity or increase the tone of the lower esophageal sphincter. Although the H₂ receptor antagonists and PPIs effectively relieve GERD symptoms, the PPIs are the treatment of choice for patients with esophagitis. Over-the-counter H₂ antagonists and PPIs are available for treatment and prevention of acid indigestion and “heartburn.”

Gastroparesis is a delay in gastric emptying stemming from diabetes or other diseases that damage gastric nerves or smooth muscle. Gastric emptying can be improved using promotility agents, which act by increasing the propulsive contractions of the stomach.

Constipation is a common symptom associated with hard or infrequent stools (fewer than three bowel movements a week), excessive straining, and a sense of incomplete evacuation. Constipation can arise from low-fiber diets, decreased mobility, treatment with certain drugs (narcotics, aluminum-containing antacids, or iron) and certain GI, metabolic, or neurologic disorders. Constipation in pregnancy is associated with a decrease in motilin and pressure from the gravid uterus. Excessive use of laxatives may lead to a reliance on laxatives for bowel movements. Dietary changes alone may be sufficient to restore normal bowel habits. However, treatment with a laxative may be indicated in patients with intermittent or chronic constipation.

Diarrhea results from the presence of excessive fluid in the intestinal lumen, generating rapid, high-volume flow that overwhelms the absorptive capacity of the colon. In most diarrheas, fluid and electrolyte absorption occur at an essentially normal rate. However, diarrhea increases fluid secretion into the lumen at a rate that exceeds its absorptive capacity, thus leading to a net accumulation of luminal fluid. Diarrhea can be acute, secondary to an enteric bacterial or viral infection, or chronic, secondary to inflammatory or functional bowel disease. The most effective way to manage diarrhea is to eliminate the infection, remove the secretagogue-producing tumor, or cure the inflammation. The major hazard associated with diarrhea is loss of fluid and electrolytes. Serious sequelae of diarrhea can generally be prevented by replacement of fluid and electrolytes. However, many patients with serious acute or chronic diarrhea require antidiarrheal therapy. Diarrhea is also common with parasitic infections (see Chapter 52).

Emesis, involving nausea and vomiting, is a normal protective mechanism to eliminate toxic substances. This process involves peripheral and central mechanisms and involves the chemoreceptor trigger zone (CTZ) in the area postrema and the nucleus of the solitary tract in the brainstem. Excessive emesis can become a pathological condition as a consequence of fluid and electrolyte loss as well as acid-induced damage to esophageal tissue. The emesis center contains receptors for several neurotransmitters, and drugs affecting these receptors are useful as antiemetics.

IBS is very common GI disorder characterized by abdominal discomfort, pain, and bloating associated with a change in bowel habit (constipation or diarrhea), which often reduces the patient’s quality of life and activity levels. For years treatment was largely ineffective and aimed at single symptom relief (altered bowel habit, abdominal pain, or bloating). Because serotonin (5-HT) and its receptors (primarily 5-HT₃) play a major role in GI function and the physiologic abnormalities in IBS, drugs that antagonize 5-HT₃ receptors have been found to provide symptom relief.

IBD describes nonspecific inflammatory disorders of the GI tract, including ulcerative colitis and Crohn’s disease, characterized by recurrent acute inflammatory episodes of diarrhea, abdominal pain, and GI bleeding. Although the exact causes of these disorders remain unknown, both appear to be immunologically mediated and influenced by genetics and environment. Treatment includes antidiarrheals, antispasmodics, and analgesics; aminosalicylates; and glucocorticoids, antibiotics, and immunomodulators (particularly azathioprine and 6-mercaptopurine as well as methotrexate, cyclosporine, and tacrolimus). The aminosalicylates have been the cornerstone of drug therapy. Infliximab, a monoclonal antibody approved for the treatment of Crohn’s disease (see Chapter 6), targets tumor necrosis factor α (TNF-α). A single infusion of infliximab induces significant improvement in patients with Crohn’s disease, and drug effects may persist for up to 12 weeks; however, long-term efficacy and safety have not been established.

Drugs used to treat diseases or disturbances of the GI tract are summarized in the Therapeutic Overview Box.

Therapeutic Overview
Problem	Treatment
Peptic ulcer disease	H₂ receptor antagonists, PPIs, sucralfate, misoprostol, antibiotics to eradicate Helicobacter pylori
Gastroesophageal reflux disease	Antacids, H₂ receptor antagonists, PPIs
Delayed gastric emptying	Promotility agents
Constipation	Laxatives
Diarrhea	Antidiarrheals
Emesis	Antiemetics
IBS	5-HT₃ receptor antagonists
IBD	Aminosalicylates, immunosuppressants, TNF-α antibodies

Mechanisms of Action

Antisecretory Drugs, Antacids, Mucosal Protectants, and Prostaglandins

The secretion of gastric acid by gastric parietal cells is regulated by histamine, acetylcholine (ACh), and gastrin (Fig. 18-2). Psychic stimuli (sight and smell of food) and the presence of food in the mouth or stomach stimulate vagally mediated acid secretion, which results from the action of ACh on parietal and paracrine cells. ACh released from secretomotor terminals of the vagus nerve acts at muscarinic M₁ receptors on paracrine cells to cause the release of histamine, which acts at parietal cell H₂ receptors to stimulate acid secretion. ACh also acts directly at parietal cell M₃ receptors to stimulate acid production (see Chapter 10). The presence of food in the stomach, which raises the antral pH, also causes gastrin to be released from gastrin-releasing cells of the antral mucosa. Circulating gastrin stimulates gastrin receptors on paracrine cells to cause the release of histamine and on gastrin receptors on parietal cells to stimulate acid production. Thus histamine release constitutes the major event in the stimulation of acid production by ACh and gastrin, and ACh and gastrin, in turn, also act directly on parietal cells to augment the actions of histamine. Histamine, released from the paracrine cells located near parietal cells in oxyntic glands, acts at parietal cell H₂ receptors to activate the H⁺,K⁺-ATPase located at the luminal membrane. Stimulation of M₃ and gastrin receptors on the parietal cell also activates this H⁺,K⁺-ATPase, which serves as the so-called proton pump that secretes H⁺ into the gastric lumen.

FIGURE 18–2 Mechanisms regulating secretion of HCl by gastric parietal cell. Receptors for acetylcholine (M₃), histamine (H₂), and gastrin (G) interact when activated by agonists to increase the availability of Ca⁺⁺ and stimulate the H⁺,K⁺-adenosine triphosphatase (ATPase) of the luminal membrane. Acid secretion can be decreased pharmacologically by blockade of M₃ receptors (1), H₂ receptors (2), intracellular cyclic adenosine monophosphate (CAMP) (3), or the H⁺,K⁺-ATPase (4).

The only important role of peripheral H₂ receptors in humans appears to be in the regulation of acid secretion. Drugs can decrease gastric secretion (see Fig. 18-2) by blocking H₂ receptors, blocking M₁ or M₃ receptors, or by inhibiting the activity of the H⁺,K⁺-ATPase in the parietal cell.

The H₂ receptor antagonists (cimetidine, famotidine, nizatidine, and ranitidine) block H₂ receptors competitively and reversibly, diminishing basal, nocturnal, and food-stimulated gastric acid secretion (Table 18-1). Although relative antisecretory potencies vary from cimetidine, the least potent, to famotidine, the most potent, increased potency does not confer greater efficacy if the drugs are given in an equipotent antisecretory dose.

TABLE 18–1 Summary of Action of the Antisecretory Drugs, Antacids, Protectants, and Prostaglandins

Category	Prototype	Mechanism of Action
Antacids	Magnesium oxide and magnesium hydroxide	Neutralize secreted acid
Anticholinergics	Propantheline	Block muscarinic receptors, decrease acid secretion
Bismuth salts	Bismuth subsalicylate	Topical antibacterial activity
H₂ receptor antagonists	Cimetidine	Block H₂ receptors, decrease acid secretion
Prostaglandins	Misoprostol	Inhibit mucosal prostaglandins, decrease acid secretion
Mucosal protectants	Sucralfate	Protect mucosal barrier
PPIs	Omeprazole	Inhibit H⁺, K⁺-ATPase, decrease acid secretion

The PPIs, omeprazole, esomeprazole (the S-enantiomer of omeprazole), lansoprazole, pantoprazole, and rabeprazole, share a common mechanism of action to inhibit parietal cell H⁺,K⁺-ATPase irreversibly, decreasing basal, nocturnal, and food-stimulated gastric acid secretion. The parent drugs are inactive, but under highly acidic conditions in the parietal cell, they are protonated and converted to active compounds that react covalently with cysteine residues in the enzyme. This inactivates the pump and prevents the transport of H⁺ into the stomach lumen (see Fig.18-2). Because all secretory stimuli ultimately cause acid production by augmenting the activity of the H⁺,K⁺-ATPase-dependent transporter, irreversible blockade of this enzyme inhibits the final step and is the most effective way to diminish acid secretion.

Anticholinergic agents block M₁ receptors on histamine-containing paracrine cells in the oxyntic mucosa to inhibit the ACh-induced release of histamine. They also block M₃ receptors on parietal cells to inhibit ACh-induced acid secretion.

Antacids are weak bases that act primarily by neutralizing intragastric hydrochloric acid. They do not decrease acid secretion. The cations (Na⁺, Ca⁺⁺, Mg⁺⁺, and Al⁺⁺⁺) initially form soluble chloride salts (Fig. 18-3). Although NaCl can be absorbed from the small intestine, the divalent ions form poorly soluble bicarbonates and carbonates, which precipitate and remain in the bowel to be excreted in the feces. The acid-neutralizing effects in the stomach lumen decrease total acid load to the duodenum and inhibit pepsin activity at an intragastric pH of 5 or above. Antacids also bind bile salts, and aluminum-containing antacids may enhance gastric cytoprotection.

FIGURE 18–3 Intragastric and intestinal interactions of prototype antacids. (1) Interaction of aluminum hydroxide with gastric acid to form soluble aluminum chloride. (2) Interaction of magnesium hydroxide with gastric acid to form soluble magnesium chloride. (3) Soluble magnesium chloride interaction with Na⁺ carbonate in the lumen of the intestine to form insoluble magnesium carbonate. (4) Interaction of soluble magnesium chloride with fatty acid salts in the lumen of the intestine to form insoluble magnesium soap. PPT, Precipitate.

Mucosal protectants such as sucralfate, an aluminum salt of sucrose octasulfate, bind electrostatically to positively charged tissue proteins and mucin within the ulcer crater to form a viscous barrier and protect the ulcer from gastric acid. Sucralfate also inhibits pepsin, binds bile salts, and stimulates production of mucosal prostaglandins. Unlike H₂ receptor antagonists and PPIs, sucralfate has no important effect on gastric acid secretion.

In parietal cells, many prostaglandins (see Chapter 15) inhibit histamine-stimulated acid secretion. Misoprostol, a synthetic prostaglandin E1 analog, modestly inhibits the concentration and total amount of acid in the gastric lumen, resulting in a reduction of basal, nocturnal, and food-stimulated acid secretion. Misoprostol also increases mucus, mucosal bicarbonate secretion, and mucosal blood flow and inhibits mucosal cell turnover, all of which enhance mucosal defense.

Eradication of H. pylori

Administration of single antimicrobial agents is not effective in eradicating H. pylori, but a combination of antibiotics and an antisecretory drug is effective. A typical regimen for eradication of H. pylori includes two antibiotics (usually clarithromycin and amoxicillin or metronidazole) and an antisecretory drug (usually a PPI). Other regimens include bismuth subsalicylate, metronidazole, tetracycline, and either a PPI or an H₂ receptor antagonist (Table 18-2). These agents can be given together or sequentially with oral probiotics to reduce adverse effects. Probiotics contain live nonpathogenic bacteria, including bifidobacteria and lactobacilli, in nonprescription products because these bacteria are found normally in the GI tract and are proposed to be beneficial in several GI disorders. The mechanism of the therapeutic effects are unknown but are proposed to improve digestive process and reduce growth of pathogenic bacteria. Probiotics induce minimal adverse effects (gas and bloating) except in immunosuppressed patients.

TABLE 18–2 Drugs Used for Eradication of H. Pylori–Associated Ulcers

Therapeutic Category	Drug Choices
Antisecretory	PPI or H₂ receptor antagonist
Bismuth salt	Bismuth subsalicylate
Nitroimidazole	Metronidazole
Antibiotic	Clarithromycin, amoxicillin, or tetracycline