Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 18 Drugs Affecting the Gastrointestinal System

MAJOR DRUG CLASSES

Antisecretory drugs

Histamine (H2) receptor antagonists

Proton pump inhibitors (PPIs)

Anticholinergic agents

Antacids

Mucosal protectants

Prostaglandins

Promotility agents

Laxatives

Antidiarrheal agents

Aminosalicylates

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.

image

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.

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

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 M1receptors 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.

image

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 M1or 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.

image

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. pyloriincludes 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

Promotility Agents

Promotility agents increase GI tract contractions and propulsion by increasing cholinergic stimuli at smooth muscle M3 receptors (Fig. 18-4). This can be accomplished by four different mechanisms, summarized in Table 18-3.

image

FIGURE 18–4 Mechanisms of promotility drugs. These agents directly or indirectly increase agonist activity at smooth muscle M3 receptors. Erythromycin is an agonist (+) at excitatory (+) motilin receptors. Metoclopramide is an antagonist (–) at dopamine (DA) D2receptors that inhibits (–) the release of acetylcholine. Neostigmine inhibits (–) hydrolysis of acetylcholine by acetylcholinesterase (AChE). Bethanechol acts directly as an agonist (+) at excitatory (+) M3 smooth muscle receptors.

TABLE 18–3 Summary of Action of Promotility Drugs

image

Cholinergic agonists and cholinesterase inhibitors increase ACh-mediated secretion at salivary, gastric, pancreatic, and intestinal secretory cells in addition to stimulation of smooth muscle cells (seeChapter 10). However, excessive secretory activity leads to significant side effects, and these drugs fail to produce closely coordinated contractions between the antrum of the stomach and the duodenum required for effective gastric emptying.

Dopamine (DA) D2 receptor antagonists block the inhibitory effects of DA to decrease ACh release. The resultant increased ACh release increases the tone of the lower esophageal sphincter (important in the therapy of GERD), increases the force of gastric contractions, improves the coordination of gastroduodenal contractions, and enhances gastric emptying. Some of these drugs are also highly effective as antiemetic agents, an action attributable to their blockade of central DA receptors in the CTZ and other sites controlling emesis.

Antagonists at 5-HT3 receptors include alosetron, ondansetron, and granisetron. Alosetron acts primarily to decrease intestinal motility, but ondansetron and granisetron have a greater antiemetic effect as they inhibit vagal afferent nerves that activate CNS emetic mechanisms. Although 5-HT4 agonists were marketed as promotility agents, these agents have proved to possess serious adverse effects and have been removed from the market.

Motilin is a GI tract hormone that participates in the initiation of migrating motor complexes that characterize the fasting motility pattern of the stomach and small intestine. Macrolide antibiotics such as erythromycin (see Chapter 46) bind to nerve and muscle motilin receptors to enhance GI tract contractions and increase gastric emptying. This promotility effect is not related to the antimicrobial activity of these drugs.

Antiemetics

Nausea and vomiting (emesis) result from a variety of causes, including adverse drug effects most prominently from anticancer drugs. The underlying cause of the emesis needs to be identified and treated with specific agents if they are available. The brainstem contains the CTZ located anatomically in the area postrema where the blood-brain barrier is essentially absent. Neurons in this brain area contain 5-HT3, D2, M1, and substance P or neurokinin (NK1) receptors. In addition, the vestibular nuclei of the brainstem also play a role in nausea, particularly motion sickness-induced nausea, and neurons in these sites express H1 and muscarinic and cannabinoid (CB) receptors. All of these receptors are targets for effective antiemetic compounds. Drugs useful as antiemetics that are discussed in other chapters in this text include D2 receptor antagonists such as prochlorperazine (Chapter 29), H1 receptor antagonists such as cyclizine (Chapter 14), muscarinic receptor antagonists such as scopolamine (Chapter 10), and less selective antiemetic agents including the antianxiety compounds such as diazepam (Chapter 31) and the glucocorticoids (Chapter 39). The pharmacokinetics and adverse effects of these agents are listed in the chapters covering these agents.

As mentioned, the 5-HT3 receptor antagonists, ondansetron and granisetron, are also effective antiemetic agents, presumable via a centrally mediated effect.

Aprepitant is a highly selective NK1 receptor antagonist in the CTZ that represents a new therapeutic class of antiemetics. Aprepitant is used with other medications to prevent nausea and vomiting as a consequence of cancer chemotherapy.

Dronabinol is a synthetic derivative of delta-9-tetrahydrocannabinol, an active compound of marijuana (cannabis), and acts as an agonist at CB receptors present in the CTZ. It is a controlled substance that is approved by the US Food and Drug Administration for the relief of nausea and vomiting, particularly associated with anticancer drugs.

Laxatives

There are several categories of laxatives (sometimes called evacuants, cathartics, or purgatives) including:

• Fiber supplements (bulk-forming)

• Emollients (stool softeners)

• Lubricants

• Saline

• Hyperosmolar agents

• Stimulants

A summary of the action of laxatives is presented in Table 18-4.

TABLE 18–4 Summary of Actions of Laxatives

Category

Prototype

Mechanism of Action

Fiber supplements

Psyllium

Increases colonic residue, stimulating peristalsis

Emollients

Docusate Na+

Lowers surface tension, allowing H2O to interact with stool

Lubricants

Mineral oil

Lubricates the stool

Hyperosmolar agents

Lactulose

Increases stool osmolarity

Saline laxatives

Magnesium hydroxide

Draws H2O into the intestine along osmotic gradient

Stimulant laxatives

Senna

Stimulates intestinal secretion and motility

Fiber supplements (bulk-forming) are nonabsorbable cellulose fibers that, when taken with H2O, become hydrated in the intestine, swell, and form a large mass that activates the defecation reflex. Intestinal transit time is reduced as a result of the increased H2O content and bulk. Natural fiber supplements (e.g., psyllium) undergo bacterial degradation in the colon, which contributes to bloating and flatulence. Semisynthetic (e.g., methylcellulose) and synthetic (e.g., polycarbophil) fibers are more resistant to bacterial degradation.

Emollients are ionic detergents that soften feces and permit easier defecation by lowering the surface tension and permitting H2O to interact more effectively with the solid stool.

Lubricants (e.g., mineral oil) are oral nonabsorbable laxatives that act by lubricating the stool to facilitate passage. Malabsorption of fat-soluble vitamins may occur with long-term use.

Hyperosmolar agents act by increasing stool osmolarity, leading to accumulation of fluid in the colon. Lactulose and sorbitol are poorly absorbed from the small intestine but undergo bacterial fermentation in the colon to organic acids and CO2. Abdominal bloating and flatulence are common side effects. Polyethylene glycol is poorly absorbed but is not metabolized by colonic bacteria. Solutions with electrolytes are used for bowel cleansing before colonoscopy. A formulation without electrolytes may be used daily.

Saline laxatives are inorganic salts, with one or both poorly absorbed cations such as magnesium, or anions such as sulfate or phosphate. Laxatives draw H2O into the intestine by osmotic means, resulting in increased GI propulsion and evacuation. Because appreciable amounts of magnesium may be absorbed, these should be avoided in patients with renal insufficiency.

Stimulant laxatives include anthraquinones such as senna, diphenylmethanes such as bisacodyl, and castor oil. The anthraquinones are converted by colonic bacteria to their pharmacologically active form, which increases fluid accumulation in the distal ileum and colon. Bisacodyl has a similar action. Castor oil is hydrolyzed by lipase in the small intestine to ricinoleic acid, which increases intestinal secretion, decreases glucose absorption, and stimulates colonic motor function through the release of neurotransmitters from mucosal enterochromaffin cells.

Antidiarrheal Drugs

Transport of fluid and electrolytes by the intestinal mucosa is regulated by neurons of the enteric nervous system and by the composition of the luminal contents. It is believed that neurons of the submucosal plexus of the intestine terminate near mucosal epithelial cells and act to increase or decrease absorption by villus cells and secretion by crypt cells. A summary of the action of antidiarrheal drugs is presented in Table 18-5.

TABLE 18–5 Summary of Action of Antidiarrheal Drugs

Category

Prototypes

Mechanism of Action

Opioids

Loperamide, diphenoxylate

Increase resistance to flow, decrease propulsion, decrease net fluid secretion

Antisecretory agents

Bismuth subsalicylate*

Decrease net fluid secretion

Gel-forming adsorbents

Hydrated aluminum silicate, pectin, kaolin

Increase resistance to flow, increase formed stools

Ion-exchange resins

Cholestyramine

Bind H2O and bile salts

* This agent has multiple actions, including antibacterial effects.

Opioids act on enteric neurons to decrease secretion and promote mucosal transport from the lumen. In addition, opioids act in the CNS to alter extrinsic neural influences on the intestine and promote a net absorption of fluid and electrolytes in addition to their analgesic effects on the CNS (see Chapter 36). Opioids also convert propulsive patterns of motility to segmenting patterns, thereby increasing resistance to flow. These actions result in slowed transit through the GI tract, allowing time for more-complete fluid absorption and leading to an increased viscosity of the luminal content. Morphine and codeine cross the blood-brain barrier and act in the brain and spinal cord to decrease transit and fluid accumulation in the intestinal lumen. Loperamide and diphenoxylate do not cross the blood-brain barrier and act locally at neural and smooth muscle sites, primarily in the submucosal plexus, to increase segmenting contractions. The increased segmenting contractions in the proximal duodenum decrease the gastroduodenal pressure gradient and delay gastric emptying.

Bismuth subsalicylate has a direct mucosal protective effect, in part, by inhibiting the formation of diarrhea-producing prostaglandins, has weak antacid properties, and possesses topical antibacterial properties. This agent has been available as a nonprescription item for many years and has proven to be quite effective, but the mechanisms for its therapeutic effects are not well understood.

Aminosalicylates

Sulfasalazine, the prototype aminosalicylate, is a conjugate of 5-aminosalicylic acid (5-ASA) and sulfapyridine linked by a diazo bond. The parent drug passes into the colon unchanged, where colonic bacteria cleave the diazo bond to form 5-ASA (the active moiety) and sulfapyridine. 5-ASA acts locally to interfere with arachidonic acid metabolism, which has a beneficial effect in IBD by an unknown mechanism. Oral preparations include agents coupling 5-ASA with compounds other than sulfapyridine (e.g., balsalazide). Delayed-release pH-dependent enteric-coated tables and time-dependent enteric-coated granules release 5-ASA proximal to the colon.

Infliximab is a monoclonal antibody against TNF-α. An infusion of infliximab significantly improves the symptoms of Crohn’s disease, and this effect can last for up to 12 weeks.

Pharmacokinetics

Pharmacokinetic parameters for selected drugs are given in Table 18-6.

TABLE 18–6 Selected Pharmacokinetic Parameters

image

H2 receptor antagonists are available orally and parenterally. They are well absorbed when given orally, but bioavailability is variable. Onset of acid inhibition occurs within 1 hour, lasts from 4 to 12 hours, and is dose-dependent. These drugs are excreted primarily unchanged in the urine; therefore dosage reduction is recommended in patients with impaired renal function.

PPIs are also available orally and parenterally. Omeprazole has a low and variable bioavailability that increases with repeated daily dosing, reaching a plateau after 3 to 4 days. The bioavailability of other PPIs is less sensitive to repeated dosing. Because PPIs bind irreversibly to parietal cell H+,K+-ATPase, they suppress gastric acid far longer than expected from their short plasma elimination half-lives. Onset of acid inhibition occurs within 1 hour but lasts from 14 to 20 hours and is dose-dependent. All PPIs undergo hepatic metabolism, and a dosage reduction is unnecessary with impaired renal function but should be considered in patients with severe liver disease.

Antacids have a rapid onset of action, but their neutralizing capacity lasts only approximately 30 minutes on an empty (fasted) stomach. If an antacid is taken after a meal, food delays gastric emptying and prolongs the antacid-neutralizing effect for up to 2 to 3 hours.

Sucralfate is available orally; only a small amount is absorbed, because most is excreted in the feces.

Sulfasalazine is absorbed partially after oral administration and excreted in the bile. The remainder passes unchanged into the colon to form 5-ASA and sulfapyridine. Most of the 5-ASA is excreted in the feces. Sulfapyridine is absorbed, metabolized in the liver, and excreted in the urine. When given as a pH-dependent enteric-coated tablet or as time-dependent granules, some 5-ASA is released in the small intestine, and absorption is increased. Topical 5-ASA exerts a local antiinflammatory effect and is available as a rectal enema.

Aprepitant is well absorbed orally, reaches maximum plasma concentrations within 4 hours, and is highly (95%) bound to plasma proteins. It undergoes extensive metabolism primarily by CYP3A4 and is also a weak-to moderate inducer of both CYP3A4 and CYP2C9. Aprepitant is eliminated by metabolism; it is not excreted via the kidneys.

Dronabinol is almost completely absorbed after a single oral dose, but due to extensive first-pass hepatic metabolism and high lipid solubility, only 10% to 20% of an administered dose reaches the circulation. Dronabinol is metabolized by microsomal hydroxylation, yielding both active and inactive metabolites. Because of its high lipid solubility, dronabinol has a large volume of distribution; it also exhibits high (97%) plasma protein binding. Dronabinol and its metabolites are excreted in both urine and feces, with biliary excretion representing the major route.

Relationship of Mechanisms of Action to Clinical Response

Antisecretory Drugs, Antacids, Mucosal Protectants, and Prostaglandins

H2 Receptor Antagonists

Cimetidine, famotidine, nizatidine, and ranitidine provide similar antisecretory effects. They all relieve PUD symptoms (e.g., epigastric pain) and GERD symptoms (e.g., acid indigestion) and promote ulcer and esophageal healing. When used as continuous maintenance therapy, they also maintain ulcer and esophageal healing. Tolerance to the gastric antisecretory effect may develop with frequent and repeated dosing and may be responsible for diminished efficacy.

PPIs

All of the PPIs provide similar antisecretory effects. Because of their potent suppression of gastric acid, PPIs provide more rapid relief of epigastric pain and heartburn and more rapid and effective ulcer and esophageal healing than the H2 receptor antagonists. They are also effective as single agents when used to maintain ulcer and esophageal healing. The PPIs are the drugs of choice for the treatment of Zollinger-Ellison syndrome. Tolerance to the antisecretory effects of the PPIs has not been reported. Rebound hypersecretion of gastric acid has been reported, but data are conflicting.

Eradication of H. pylori

Treatment of H. pylori is susceptible to many antimicrobial agents in vitro, but it has proved difficult to eradicate the infection with single agents in humans. The PPI-based three-and four-drug regimens (see Table 18-2) are successful in approximately 80% to 90% of patients. H. pylori organisms have been shown to develop resistance to nitroimidazoles (e.g., metronidazole) and macrolides (e.g., clarithromycin), but resistance to tetracycline and amoxicillin is uncommon. Therefore eradication regimens should contain at least two antimicrobial agents.

Anticholinergics

Anticholinergics are effective in reducing gastric acid secretion, but high dosages are required to heal peptic ulcers, resulting in significant adverse effects.

Antacids

Antacid neutralization provides almost immediate relief of symptoms, but large volumes and frequent dosing are necessary for mucosal healing. The neutralizing effects occur for as long as the antacids are present in the stomach. Because of their side effects, disagreeable taste, and poor compliance, antacids are not used as single agents to heal peptic ulcers or esophagitis. They are used primarily for the occasional relief of acid indigestion, epigastric pain, and heartburn.

Mucosal protectants

Sucralfate heals peptic ulcers as effectively as the H2 receptor antagonists with a minimum of adverse effects. Because sucralfate has no important effect on intragastric pH, it is not very effective in relieving acid-related symptoms or in healing esophagitis. The use of sucralfate has decreased with the introduction of more effective drugs such as the PPIs.

Prostaglandins

Misoprostol exerts both a gastric antisecretory effect and a protective effect on the gastric and duodenal mucosa. Its primary therapeutic effect, however, is thought to be related to stimulation of mucosal defense mechanisms. Misoprostol is effective in reducing the risk of NSAID-induced peptic ulcers, but significant adverse effects limit its use.

Promotility Drugs

Promotility drugs are used to increase gastric emptying in the treatment of diabetic gastroparesis and to increase the tone of the lower esophageal sphincter in the management of GERD. Some, such as metoclopramide, also exhibit significant antiemetic activity and are used in patients receiving antineoplastic drugs. Tolerance to the promotility effects of metoclopramide may develop and render the drug ineffective. Promotility agents devoid of DA antagonist activity produce antiemetic effects by exerting an antagonist action at 5-HT3 receptors, indicating that local gastric effects may be important in the suppression of emesis. Ondansetron and granisetron are more effective than other promotility drugs in decreasing the nausea and vomiting associated with antineoplastic agents. Erythromycin has little antiemetic activity but is an effective promotility drug.

Antiemetics

The antiemetic aprepitant is indicated for nausea and vomiting associated with cancer chemotherapy and for postoperative nausea and vomiting. It augments the antiemetic effects of both the 5-HT3 receptor antagonist ondansetron and the glucocorticoid dexamethasone and inhibits both acute and delayed emesis associated with cisplatin-induced emesis.

Dronabinol is indicated for cancer chemotherapy-associated nausea and vomiting in patients who fail to respond to other conventional treatments.

Laxatives

Fiber supplements soften feces and are effective for treating mild constipation and IBS. Beneficial effects typically take approximately 1 week to be manifest. Emollients also soften feces and permit easier defecation but are not very effective laxatives. The hyperosmolar agents, lubricants, and saline laxatives usually work within a day, whereas stimulant laxatives are effective within hours but may cause abdominal cramping.

Antidiarrheal Drugs

Opioids

The opioid antidiarrheal drugs are remarkably effective in the management of acute diarrhea. Those with CNS activity should be used cautiously for acute diarrhea and should not be used for the management of chronic diarrhea. The most effective antidiarrheal drugs are morphine, codeine, loperamide, and diphenoxylate. Morphine and codeine are highly addictive controlled substances (Chapter 37), whereas the synthetic agent loperamide, which is not a controlled substance and is available by prescription, is widely used and is effective for the control of diarrhea caused by IBS or IBD. Opioid antidiarrheal agents should not be used in the symptomatic treatment of diarrhea caused by enteric infections, especially those caused by Shigella or Salmonella.

Bismuth Subsalicylate

Bismuth subsalicylate is an effective antidiarrheal agent especially useful against enterotoxigenic strains of E. coli. It is sometimes included for its antimicrobial properties in therapy directed against H. pylori.

Gel-Forming Substances

Substances that form semisolid gels within the intestinal lumen increase resistance to flow and also increase the firmness of stools. Typical gel substances include kaolin and pectin, which form clay-like gels when hydrated. They do not, however, reduce the volume of fluid excreted and thus have little therapeutic benefit.

5-HT3 Receptor Antagonists

5-HT3 receptor antagonists, such as alosetron, decrease the frequency of bowel movements and improve stool consistency. Abdominal pain and bloating are also reduced in patients with IBS. 5-HT4receptor agonists, such as tegaserod and cisapride, increase the frequency of bowel movements and improve stool consistency; however, the availability of these agents has been suspended in the United States because of serious adverse cardiovascular effects.

Aminosalicylates

Sulfasalazine and the newer aminosalicylate forms are effective in treating mild to moderate ulcerative colitis and Crohn’s disease. The forms that release 5-ASA in the small intestine are more likely to be effective in patients with ileal involvement. Symptomatic improvement in abdominal pain and diarrhea is seen in approximately 3 weeks. Lower daily dosages are effective in maintaining remission. Topical 5-ASA rectal enemas are effective in treating ulcerative proctitis and proctosigmoiditis.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

The clinical problems associated with drugs used for the treatment of GI disorders are summarized in the Clinical Problems Box. As mentioned, 5-HT4 agonists (tegaserod and cisapride) are no longer available in the United States because of serious adverse cardiovascular events. This is an example where a publicly promoted drug for treating IBS had to be suspended because of increased pharmacovigilance by the U.S. Food and Drug Administration.

Antisecretory Drugs, Antacids, Mucosal Protectants, and Prostaglandins

H2 Receptor Antagonists

The H2 receptor antagonists a have a low incidence of adverse effects, unrelated to their blockade of H2 receptors. The most common side effects are similar for all H2 receptor antagonists and include headache, diarrhea, constipation, flatulence, and nausea. Dizziness, somnolence, lethargy, agitation, and confusion occur occasionally with these drugs. Risk factors include renal impairment and advanced age. Transient skin rashes have been observed in a small number of patients. Most adverse effects disappear with continued treatment or upon discontinuation of the drug. Cimetidine, but not famotidine, nizatidine, or ranitidine, binds to testosterone receptors and exerts antiandrogenic effects, resulting in decreased libido, decreased sperm count, impotence, and gynecomastia in men. These antiandrogenic effects are associated with high doses and long-term use. Cimetidine also interferes with drugs metabolized by hepatic CYP enzymes. Thus the use of cimetidine in conjunction with drugs metabolized by this system can lead to elevated plasma concentrations and toxic responses to these other drugs. Because famotidine, nizatidine, and ranitidine do not bind substantially to cytochrome P450 isoenzymes, they do not produce this problem. All H2 receptor antagonists increase intragastric pH and may decrease the bioavailability of drugs that require gastric acidity for absorption such as ketoconazole.

PPIs

The PPIs are well tolerated and have a low incidence of adverse effects. The most common side effects are similar to those observed with the H2 receptor antagonists. Diarrhea has been reported more frequently with lansoprazole and omeprazole and appears to be dose-related. Most antisecretory drugs increase fasting and postprandial serum gastrin as a function of their acid-inhibiting effect. The profound effects on acid secretion and the resultant hypergastrinemia in patients taking PPIs have raised concern regarding their long-term use and the potential for causing gastric mucosal hyperplasia and cancer. However, no significant hyperplasia or gastric cancer has been observed in humans taking PPIs for greater than 15 years. Omeprazole and esomeprazole may interfere with drugs metabolized by hepatic CYP2C (e.g., warfarin, phenytoin, diazepam), but toxicities are uncommon. All PPIs increase intragastric pH and may also decrease the bioavailability of drugs that require gastric acidity for absorption.

Antacids

The most common problems encountered in patients taking antacids are constipation (with aluminum-containing antacids) and diarrhea (with magnesium-containing antacids). An acceptable balance in stool frequency and consistency can be achieved by using agents that include mixtures of magnesium and aluminum salts or by alternating doses of magnesium- or aluminum-containing antacids. Ca++, Mg++, and Al+++ are usually poorly absorbed, but systemic toxicity can be manifest in patients with renal insufficiency. Calcium salts can produce systemic hypercalcemia, with the resultant formation of calculi (milk alkali syndrome). Aluminum can bind phosphate in the GI lumen and reduce the absorption of phosphate, leading to phosphate deficiency with muscle weakness and reabsorption of bone. Most antacids have been reformulated to contain little or no Na++. All antacids increase intragastric pH and may decrease the bioavailability of drugs that require gastric acidity for absorption. Aluminum-containing antacids may inhibit the absorption of tetracycline and iron supplements. Systemic antacids such as NaHCO3 are absorbed into the blood and have the potential to increase blood pH and alkalinize urine.

Mucosal Protectants

Sucralfate is virtually devoid of systemic side effects because it not readily absorbed. Constipation occurs in a small number of patients and is related to the aluminum salt. Aluminum may also bind dietary phosphate, leading to a phosphate deficiency. Sucralfate may bind to drugs such as the quinolone antibiotics, warfarin, and phenytoin and limit their absorption.

Prostaglandins

Prostaglandins, such as misoprostol, induce diarrhea by promoting secretion of fluid and electrolytes into the bowel lumen and by inhibiting the intestinal segmenting contractions that retard the flow of luminal contents. Prostaglandins also increase intestinal secretion, leading to a net luminal fluid accumulation. Diarrhea occurs frequently, is dose-related, and often limits use of the drug. Misoprostol also stimulates uterine contractions and may endanger pregnancy and should be used with caution in women of child-bearing age. It is contraindicated in pregnancy.

Bismuth Subsalicylate

Bismuth subsalicylate temporarily turns the tongue and stool black and can cause tinnitus, especially when taken with other salicylate-containing drugs (e.g., aspirin, 5-ASA).

Promotility Agents

Cholinergic agonists produce a variety of side effects typically associated with cholinergic stimulation (see Chapter 10).

Metoclopramide can induce dystonia or parkinsonian side effects because of its activity as a DA receptor antagonist (see Chapter 28). DA receptor antagonists also can induce symptoms of hyperprolactinemia, consisting of gynecomastia, galactorrhea, and breast tenderness. Metoclopramide also often induces sedation.

As mentioned, cisapride and tegaserod produce severe cardiovascular adverse effects.

Erythromycin is a macrolide antibiotic that also has promotility effects related to activation of motilin receptors.

Antiemetics

Adverse effects associated with the use of the 5-HT3 receptor antagonists include constipation or diarrhea, headache, and light-headedness. Adverse effects of antiemetic agents that block DA, histamine, and muscarinic receptors are discussed in the chapters pertaining to these agents.

The adverse effects of the NK1 antagonist aprepitant include fatigue, constipation, diarrhea, anorexia, nausea, and hiccups. As mentioned, aprepitant induces both CYP3A4 and CYP2D9 and has been shown to alter the metabolism of both warfarin and tolbutamide.

The cannabinoid dronabinol has effects on the CNS to increase sympathetic activity and may lead to tachycardia; orthostatic hypotension is not uncommon. Dose-related effects on appetite, mood, cognition, and memory have also been reported and appear to be highly individual-dependent. Dronabinol is a schedule III drug and has been shown to produce psychological and minor degree of physiological dependence (see Chapter 37).

Laxatives

Fiber supplements (especially the natural fibers such as psyllium) and lactulose may cause abdominal fullness, bloating, and flatulence. Stimulant and saline laxatives may cause abdominal cramping, watery stools, dehydration, and fluid and electrolyte imbalances. In patients with renal insufficiency or cardiac dysfunction, saline laxatives may cause electrolyte and volume overload. A brown-black pigment (melanosis coli) may develop in the colon of patients taking anthraquinones but does not lead to the development of colon cancer. Laxatives should never be prescribed for patients with undiagnosed abdominal pain or intestinal obstruction. Because castor oil causes severe intestinal cramping and diarrhea, its use should be avoided.

Antidiarrheals

The adverse effects of the natural (morphine and codeine) and synthetic (loperamide and diphenoxylate) opioids are discussed in Chapter 36. Diphenoxylate crosses the blood-brain barrier poorly under normal conditions and in usual therapeutic doses does not produce CNS side effects. However, in an overdose it can cause respiratory depression, which can be reversed by naloxone. Diphenoxylate is available in combination with atropine, the latter added to deter abuse. Loperamide traverses the blood-brain barrier poorly and therefore has virtually no CNS effects and a low abuse potential.

5-HT3 Receptor Antagonists

The most common side effect associated with alosetron is constipation.

Aminosalicylates

The side effects associated with sulfasalazine may be dose-dependent or dose-independent. Dose-dependent effects correlate with sulfapyridine in the blood and include nausea, loss of appetite, headache, malaise, and diarrhea. Dose-independent effects include hypersensitivity reactions typical of sulfonamides. Skin rashes occur occasionally and require that the drug be discontinued. Fever, hemolytic anemia, pulmonary complications, hepatitis, and pancreatitis have been reported. A hypersensitivity reaction has been reported in patients taking 5-ASA dosage forms. Patients allergic to aspirin should not take 5-ASA. The potential for renal damage exists in patients taking high doses of 5-ASA.

CLINICAL PROBLEMS

Antacids

Aluminum salts

Constipation

Magnesium salts

Diarrhea

Mg++ absorption

Sodium salts

Increased plasma Na+ concentration

Bismuth Subsalicylate

Black tongue and stool

Tinnitus

H2 Receptor Antagonists

Cimetidine

Interference with metabolism of many drugs

Antiandrogenic effect, e.g., gynecomastia, impotence, decreased sperm count

Laxatives

Saline

Mg++ absorption

Lubricants (mineral oil)

Decreased absorption of fat-soluble vitamins

Pulmonary aspiration

Stimulants

Abdominal cramping

Watery diarrhea

Proton Pump Inhibitors (PPIs)

Gastric mucosal hyperplasia

Promotility Drugs

Bethanechol, neostigmine

Excess GI secretions, cramps, cholinergic stimulation

Metoclopramide

Extrapyramidal effects

Hyperprolactinemia

Prostaglandins

Misoprostol

Diarrhea

Uterine stimulation

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Aminosalicylates

Balsalazide (Colazal)

Mesalamine, 5-ASA (Asacol, Canasa, Lialda, Pentasa, Rowasa)

Sulfasalazine (Azulfidine, Sulfazine)

Antacids

Aluminum hydroxide (AlternaGEL, Amphojel, Dialume)

Aluminum hydroxide/magnesium hydroxide/simethicone (Mylanta)

Calcium carbonate (Tums)

Magaldrate (Lasospan, Lowsium, Maoson, Riopan, RonAcid)

Magnesium hydroxide (Milk of Magnesia)

Simethicone (Mylicon)

Bismuth Salts

Bismuth subsalicylate (Pepto-Bismol)

Cannabinoid Antagonist Antiemetics

Dronabinol (Marinol)

Dopamine D2 Receptor Antagonists

Prochlorperazine (Compazine, Compro)

Histamine H1 Receptor Antagonists

Cyclizine (Marezine)

Histamine H2 Receptor Antagonists

Cimetidine (Tagamet)

Famotidine (Mylanta, Pepcid)

Nizatidine (Axid)

Ranitidine (Zantac)

Laxatives

Castor oil (Emulsoil, Neoloid, Purge)

Lactulose (Chronulac)

Methylcellulose (Citrucel)

Polycarbophil (Fibercon)

Psyllium (Metamucil)

Mucosal Protectants

Sucralfate (Carafate)

Neurokinin NK1 Antagonist

Aprepitant (Emend)

Opiate Antagonists

Diphenoxylate/atropine (Lomotil, Lonox)

Loperamide (Imodium)

Proton Pump Inhibitors (PPIs)

Esomeprazole (Nexium)

Lansoprazole (Prevacid)

Omeprazole (Prilosec)

Pantoprazole (Protonix)

Rabeprazole (Aciphex)

Promotility Agents

Erythromycin (E-Mycin)

Granisetron (Kytril)

Metoclopramide (Octamide, Reglan)

Serotonin 5-HT3 Antagonists

Alosetron (Lotronex)

Granisetron (Kytril)

Ondansetron (Zofran)

New Horizons

Newer antibodies against TNF-α are in clinical testing for IBD. Cytokine-based therapies, probiotics, helminth ova therapy, and stem-cell transplantation are also under development for IBD. Developing therapies for GERD include new PPI isomers, K+ competitive acid blockers, and inhibitors of transient lower esophageal sphincter relaxation.

It is important to note that with advances in genomics, pharmacogenomic factors have been observed in GI disorders. In IBD, polymorphisms related to the enzyme caspase have been reported. In addition, variants in immune-related genes that lead to an excessive immune response to normal bacteria have also been identified. In IBS, polymorphisms in genes encoding a variety of neurotransmitter receptors, the serotonin transporter gene, and genes encoding immunology-related proteins have been implicated.

FURTHER READING

Drugs for irritable bowel syndrome. Treat Guidel Med Lett. 2006;4:11-16.

Probiotics. Med Lett. 2007;49:66-68.

Proton pump inhibitors for GERD in children. Med Lett. 2007;49:17-18.

Summers RW. Novel and future medical management of inflammatory bowel disease. Surg Clin North Am. 2007;87:727-741.

SELF-ASSESSMENT QUESTIONS

1. Cimetidine and related antisecretory drugs act as antagonists at parietal cell:

A. M3 receptors.

B. Prostaglandin receptors.

C. H2 receptors.

D. H1 receptors.

E. Gastrin receptors.

2. Metoclopramide produces promotility and antiemetic effects primarily because it acts as an:

A. Antagonist at M2 receptors.

B. Inhibitor of acetylcholinesterase.

C. Agonist at motilin receptors.

D. Antagonist at D2 receptors.

E. Antagonist at 5-HT3 receptors.

3. Which one of the following is most likely to interfere with cytochrome P450 drug metabolism?

A. Cimetidine

B. Ranitidine

C. Pantoprazole

D. Sucralfate

E. Metoclopramide

4. Which one of the following is most likely to induce parkinsonism-like extrapyramidal symptoms?

A. Sulfasalazine

B. Ranitidine

C. Omeprazole

D. Sucralfate

E. Metoclopramide

5. Major serious side effects associated with the long-term use of an aluminum-containing antacid include:

A. Diarrhea.

B. Systemic alkalosis.

C. Phosphate depletion.

D. Kidney stones.

E. Dementia.

6. Dry mouth, visual disturbance, constipation, and difficulty in urination are side effects commonly associated with use of:

A. Muscarinic receptor antagonists.

B. H2 receptor antagonists.

C. D2 receptor antagonists.

D. 5-HT3 receptor antagonists.

E. Gastrin receptor antagonists.