CHAPTER 33 Drugs Acting on the Gastrointestinal Tract
Drugs that exert an effect on the gastrointestinal tract are among the most frequently used drugs. Digestive diseases are estimated to affect 60 to 70 million people in the United States each year with an annual direct cost of more than $85 billion.23 There is a high likelihood that a patient coming into the dental office may be on a regimen of one or more of these agents. Included in this group of drugs are anticholinergics, antihistamines, antacids, proton pump inhibitors (PPIs), antiemetics, laxatives, antidiarrheal or antispasmodic drugs, and gastrointestinal stimulants. Some of these drugs are available over-the-counter (OTC) without prescription and may be used at the discretion of the patient.
Dentists are likely to prescribe these some of these drugs to modify salivary gland function or reduce nausea and vomiting. Knowledge that the patient is taking these drugs helps the dental provider to understand the patient’s medical situation better, guides treatment decisions such as chair position, and may influence the choice of a dental therapeutic agent. A gastrointestinal disturbance arising during the course of dental treatment may be attributable to, or managed by, one of these agents.
Many of the drugs discussed here are described in detail in other parts of the book. This chapter focuses on drugs used exclusively for their effect on the gastrointestinal tract and drugs with a wider spectrum of activity that have application to gastrointestinal disorders. Drugs that act on the gastrointestinal tract and are commonly used in dentistry to modify salivary gland activity or to reduce drug-induced nausea and vomiting are listed in Table 33-1.
|THERAPEUTIC USE||DRUG||DOSE (mg)*|
|Sialagogue||Pilocarpine hydrochloride (Salagen)||5†|
|Cevimeline hydrochloride (Evoxac)||30†|
|Antisialagogue||Atropine sulfate (Sal-Tropine)||0.3-1.2|
|Scopolamine hydrobromide (Scopace)||0.4-0.8|
|Meclizine hydrochloride (Antivert)||25-50|
|Promethazine hydrochloride (Phenergan)||25|
Acid-peptic conditions such as heartburn (pyrosis), dyspepsia (indigestion), gastroesophageal reflux, and peptic ulcer disease (PUD) (gastric and duodenal) are often treated with drugs that either reduce intragastric acidity or promote gastrointestinal mucosal defense. In all these conditions, patient discomfort primarily results from the caustic effects of the gastric acid on the esophagus or from overcoming the gastrointestinal mucosal defense system or both. In the United States, heartburn has been reported to occur at least once a month by 44% of adults, at least weekly by 14%, and at least daily by 7%.12 Heartburn is a common term to describe a burning sensation that usually arises from the lower chest area (substernal) and moves upward toward the neck. It most commonly occurs within 2 hours after eating or when lying down or bending over. The symptoms are caused by the abnormal reflux of gastric contents or vapors retrograde into the esophagus. Heartburn that is frequent and persistent is the most common symptom of gastroesophageal reflux disease (GERD). GERD is one of the most prevalent digestive diseases among adults in the United States with more than 19 million cases annually.25 Symptoms arising from GERD, such as heartburn, are among the most common reasons for visits to primary care physicians.
PUD is a common malady affecting 10% to 15% of the population at some time in life. In a given year, nearly 15 million people in the United States have PUD.23 Although PUD is a painful condition that can seriously affect the quality of life, it is rarely fatal. Economically it is a major illness, with annual direct costs in the United States of greater than $3 billion, not including dollars lost in decreased wages and work productivity.25 Peptic ulcers are characterized by spontaneous healing and recurrence. The primary complication is hemorrhage, which may be life-threatening if undetected or ignored. Perforation of the gastrointestinal wall, which occurs much less frequently, accounts for most of the more than 4000 deaths from this disease each year in the United States.10
Throughout most of the twentieth century, therapy for PUD was directed at suppression of acid secretion or neutralization of secreted acid. This approach was based on the erroneous assumption that ulcers develop only because of increased gastric acid secretion. The primary causes of PUD are now known to be related to mucosal exposure to gastric acid and pepsin with a very strong association with Helicobacter pylori infection or the breakdown of normal mucosal defenses from the use of nonsteroidal anti-inflammatory drugs (NSAIDs).10 H. pylori infects more than half of the U.S. population older than 50 years and accounts for 80% of all stomach ulcers and greater than 90% of all duodenal ulcers.3 Because only a relatively small percentage of H. pylori–infected patients develop PUD in their lifetime, other factors must play a role in the development of this disease. Although H. pylori is found in saliva, the relationship between its presence in the mouth and infection in the stomach is unknown. The oral cavity may be a permanent reservoir for H. pylori, and a person-to-person route is the most probable mode of transmission.26
PPIs are drugs that irreversibly inhibit H+/K+-activated adenosine triphosphatase (H+,K+-ATPase, commonly called the proton pump) in the gastric parietal cell (Figure 33-1), the final common pathway for acid secretion. PPIs have become the drug class of choice for treating acid-related gastrointestinal diseases such as PUD and GERD. PPIs are among the most widely selling drugs because of their outstanding efficacy and safety. Currently, five members of the PPI class are available by prescription in the United States: esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole (Table 33-2). Omeprazole is available OTC. When taken orally, all five agents effectively reduce basal and stimulated acid secretion considerably. They are longer lasting and substantially more potent than histamine H2-receptor antagonists in the short-term treatment of PUD and GERD and relief of heartburn.
FIGURE 33-1 The physiologic control of H+ secretion by the gastric parietal cell, with the site of action of the major antisecretory drugs. Included is an endocrine cell that secretes histamine (enterochromaffin-like [ECL] cell) and an acid-secreting parietal cell.
PPIs are administered as inactive prodrugs that accumulate selectively in the acid environment of the secretory canaliculus of the gastric parietal cell. The PPI is rapidly protonated and converted to the active form of the drug. Because PPIs bind covalently to active proton pumps, synthesis of new pumps or activation of resting pumps is required to restore activity. This irreversible inhibition of the pump explains why the duration of action of this class extends beyond the elimination half-life of 0.5 to 2 hours (see Table 33-2). PPIs are best taken on an empty stomach (food can decrease bioavailability up to 50%) once daily 1 hour before a meal so that the peak serum concentration coincides with the maximum activation of the proton pumps.
The most common adverse effects reported with PPIs are headache, diarrhea, and nausea, but the frequency is only slightly greater than placebo. Long-term use of PPIs may cause a slight increase in serum gastrin. This information led to concerns regarding gastrin-induced neoplasms that have been reported in animal models. PPIs have been available for more than 20 years and, to date, none have been associated with an increased risk of gastric cancers in patients receiving long-term therapy. Of more recent concern are reports that PPIs, particularly at high doses, are associated with an increased risk of hip fracture by interfering with Ca++ absorption through induction of hypochlorhydria31 and with an increased risk to develop community-acquired Clostridium difficile–associated disease (CDAD).22
All PPIs increase gastric pH and may alter the absorption of drugs that are weak bases or acids or formulated as pH-dependent, controlled-release products. Absorption of aspirin, digoxin, and midazolam may be increased, and ketoconazole absorption may be decreased when administered with a PPI. The clinical significance of the alterations is unclear. PPIs can also alter the hepatic metabolism of other medications. All PPIs are metabolized to varying degrees by hepatic P450 cytochromes, including CYP2C19 and CYP3A4, and may interfere with the medications metabolized by these same enzymes. Omeprazole has been shown to progressively inhibit CYP2C19 activity with repeated administration and may inhibit the metabolism of diazepam, warfarin (Coumadin), and phenytoin.24 Despite these concerns, few clinically significant drug interactions have been reported given the enormous popularity of PPIs.
Histamine is one of the primary mediators of gastric acid secretion, along with acetylcholine and gastrin. The final common pathway is through the proton pump (see Figure 33-1). As discussed in Chapter 22, H2 receptors are located on the membranes of acid-secreting parietal cells of the stomach. H2 receptor antihistamines (commonly called H2 blockers) are reversible, competitive antagonists of histamine at the H2 receptors. The duration and the degree of acid suppression are dose-dependent. These are highly selective agents in that they do not affect the H1 receptors and are not anticholinergic. Cimetidine, the first of these drugs to be used widely, revolutionized the treatment of duodenal ulcers. With the recognition of the role of H. pylori in PUD and the introduction of PPIs, the use of H2 antagonists has markedly declined.
A usual single dose of any of the H2 antagonists currently available for prescription or nonprescription use in the United States, including cimetidine, famotidine, nizatidine, and ranitidine (Table 33-3), inhibits 60% to 70% of total 24-hour acid secretion. These agents are particularly effective in inhibiting nocturnal acid secretion, which is stimulated more by histamine. Food-induced gastric acid secretion is stimulated more by gastrin and acetylcholine and is less inhibited by the H2 blockers.
H2 antagonists, in addition to their antisecretory actions, also accelerate ulcer healing by the induction of endogenous prostanoid synthesis. Patients with untreated duodenal ulcers have significantly lower gastric prostanoid synthesis than occurs in normal subjects, and patients on long-term NSAID therapy show almost complete inhibition of prostanoid synthesis by gastric mucosa. These findings suggest that decreased endogenous prostanoid synthesis may contribute to the pathogenesis of mucosal damage.
H2 blockers are commonly administered orally. The antisecretory activity usually begins within 1 hour of administration and persists for 6 to 12 hours. They have an oral bioavailability of 40% to greater than 90%, achieve peak plasma concentrations in 0.5 to 3 hours, and are eliminated with a terminal half-life of 1.5 to 3 hours (see Table 33-3). The drugs undergo partial metabolism in the liver; the remainder of the parent drug is eliminated unchanged by the kidney. The duration of effectiveness varies with the drug, dose, and medical condition being treated, ranging from 4 hours for a low dose of cimetidine for hypersecretory disorders to 24 hours for all these agents when used to treat duodenal and gastric ulcers.
Comparative studies of H2 blockers show that the four drugs in this class are essentially equal in clinical effectiveness regarding ulcer treatment even though they express varying potencies in their ability to block pentagastrin-stimulated gastric acid secretion in the research laboratory. Cimetidine seems unique among H2 blockers in exerting biologic effects that are unrelated to gastric H2 occupancy. Cimetidine therapy, particularly when prolonged and at high doses, can cause antiandrogenic effects. These reversible effects result from the ability of cimetidine to compete with dihydrotestosterone at androgen-binding sites and to inhibit the CYP metabolism of estradiol.13 Men treated with high doses of cimetidine for long periods may experience impotence and development of gynecomastia, whereas women may develop galactorrhea. Substitution of ranitidine for cimetidine reverses these effects; no antiandrogenic effects have been reported after therapeutic doses of famotidine or nizatidine.
Of importance to the dentist is the ability of cimetidine to decrease the hepatic oxidative biotransformation of many other drugs, including lidocaine and diazepam. Cimetidine and ranitidine are ligands for multiple CYP enzymes (see Table 2-3), with cimetidine exhibiting a much higher affinity and inhibiting hepatic microsomal enzyme activity to a much greater extent. The clinical use of ranitidine, famotidine, and nizatidine does not seem to have a significant effect on the metabolism and elimination of other drugs.
The widespread use of cimetidine has revealed various central nervous system (CNS) manifestations (e.g., headache, lethargy, confusion, forgetfulness), especially in elderly patients. Impaired renal function in an older patient may contribute to these reactions. Similar effects have been reported for ranitidine and famotidine but seem to be less common.
The evidence that PUD (and gastritis and possibly gastric adenocarcinoma) is directly linked to infection by the gram-negative organism H. pylori is now well established. Cultures taken from biopsy material are positive for H. pylori in approximately 95% of duodenal ulcer specimens and 75% of biopsy specimens taken from gastric ulcers compared with a roughly 25% incidence in asymptomatic control subjects.5
These findings have led to the routine use of antibiotic therapy for the eradication of gastric and duodenal ulcers. Significant reductions in clinical symptoms and histologic evidence of ulcers have been achieved. The current cornerstone of therapy for H. pylori–associated peptic ulcers involves a triple regimen of a PPI (e.g., lansoprazole) with dual antibiotics clarithromycin and amoxicillin. This treatment regimen results in eradication of the organism in greater than 80% of patients,9 although the success rate has been declining because of increasing clarithromycin resistance.6 PPIs not only add antisecretory properties, but may also enhance healing through direct anti–H. pylori properties. Other therapeutic approaches include adding bismuth subsalicylate to the regimen (quadruple therapy) or substituting a different antibiotic such as levofloxacin or metronidazole.9 For patients with NSAID-induced PUD, rapid healing is often initiated with the use of a PPI and discontinuation of the NSAID. Future studies are required to determine the exact interaction between bacterial infection and other prognostic factors (e.g., smoking, alcohol, NSAIDs) implicated in ulcer formation.
Gastric antacids are weak bases that buffer or neutralize gastric hydrochloric acid (HCl) to form a salt and water and reduce gastric acidity. They are useful in the treatment of PUD, heartburn, GERD, and dyspepsia caused by overeating or eating certain foods. Through acid neutralization, antacids also secondarily reduce the proteolytic activity of pepsin, which is completely inactivated at a pH greater than 4. Overuse of antacids is discouraged because excessive neutralization may stimulate acid rebound; this response may be of little clinical significance because the added acid load likely is compensated by the buffers in the antacid. All antacids may affect the absorption of other medications by directly binding to the drug or increasing the intragastric pH, altering the drug’s dissolution/solubility. In particular, antacids should not be given within 2 hours of a dose of a tetracycline or fluoroquinolone antibiotic.
Antacids may also enhance ulcer healing independent of their acid-neutralizing property by enhancing the gastric mucosal defense mechanisms. They may stimulate prostaglandin production or bind unidentified substances that may be injurious to the mucosa, or both. Prostaglandins are known to inhibit gastric acid secretion and exert cytoprotective properties. Taken together, the overall effect of antacid therapy is far more complex than simple acid neutralization.
Antacids have a rapid onset of action that depends on how fast the product dissolves in gastric acid. In general, antacid suspensions dissolve more easily than tablets or powders for a faster response. The duration of action of an antacid in the stomach is influenced by the gastric emptying time, which is slowed by food in the stomach and patient variability in gastric secretory capacity. In general, antacids taken on an empty stomach have a duration of action of approximately 30 minutes, whereas antacids taken after a full meal may neutralize acid for 3 hours. Four primary compounds are currently used, alone or in combination, in antacid products: sodium bicarbonate, Mg++ salts, aluminum salts, and calcium carbonate. Following is a discussion of these commonly used antacid preparations:
Sodium bicarbonate is widely available in the form of baking soda and combination products. It reacts almost instantaneously to neutralize HCl to produce CO2 and NaCl. The formation of CO2 results in belching and gastric distention. Sodium bicarbonate is referred to as a “systemic” antacid because the unreacted fraction is readily absorbed into the general circulation and may alter systemic pH. The potential for Na+ overload and systemic alkalosis limits its use to short-term relief of indigestion. Na+ overload resulting from repeated use of large doses may contribute to fluid retention, edema, hypertension, congestive heart failure, and renal failure. Sodium bicarbonate is contraindicated in patients on a low-salt diet.
Several Mg++ salts (carbonate, hydroxide, oxide, trisilicate) have antacid properties. Magnesium hydroxide (milk of magnesia) is used most often and has a more rapid onset of action and high neutralizing capacity. It reacts slowly with HCl to form MgCl2 and water. No CO2 is generated. The risk of Mg++ overload is low and significant only in patients with impaired renal function. A disadvantage is its laxative effect, and few ulcer patients can tolerate it as the sole antacid for any length of time.
Magnesium trisilicate is much weaker than magnesium hydroxide, and substantially more of the drug is required for the same degree of neutralization. Its onset of action is slow, and it reacts with gastric acid to form silicon dioxide in the stomach. Silicate kidney stones have been reported after its prolonged use. It is generally used in combination with other antacids, such as aluminum hydroxide, calcium carbonate, and magnesium carbonate.
Aluminum may be administered in several salt forms (aminoacetate, carbonate, hydroxide, phosphate), but aluminum hydroxide gel is the most potent buffer and most frequently used. Aluminum hydroxide dissolves slowly, is poorly absorbed, and reacts with HCl to form AlCl3 and water. As with the Mg++ salts, no CO2 is generated. Liquid formulations provide a more rapid response than solid forms. Other than occasional nausea and vomiting, toxicity is rare. The formation of insoluble salts limits its absorption. Patients with impaired renal function who take aluminum antacids long-term may not clear the Al+++ resulting in hyperalbuminemia and accumulation of Al+++ in other tissues. The most common side effect is constipation, which may lead to intestinal obstruction. The constipating effect of aluminum-containing antacids is dose-related and can be managed with stool softeners or laxatives or minimized when the drug is taken with magnesium hydroxide. Because Al+++ can combine with phosphate in the gut to form insoluble aluminum phosphate, which is then excreted in the feces, prolonged use of large doses of aluminum hydroxide may result in phosphate depletion, particularly when phosphate intake is low. Anorexia, malaise, and muscle weakness are characteristic of phosphate depletion.
Calcium carbonate produces a potent and prolonged neutralization of HCl forming CO2 and CaCl2. Approximately 90% of the ingested Ca++ forms insoluble salts in the gut and is excreted in the feces. The remaining Ca++ is absorbed into the systemic circulation. Extensive use of Ca++-containing antacids may cause or exacerbate hypercalcemia, which is characterized by neurologic symptoms and reduced renal function. This effect is rare in healthy patients with normal renal function. Ca++-containing antacids are associated with acid rebound and increased serum gastrin concentrations. These effects have not been shown to delay ulcer healing and may be caused by a direct effect of Ca++ on the gastric mucosa.25 Calcium carbonate has a chalky taste and may produce constipation, which reduces its desirability as an antacid. Because some Ca++ is absorbed, Ca++-containing antacids may be marketed as a source of dietary Ca++.
Alginic acid is not an antacid, but because of its unique mechanism of action it is added to various antacid preparations to increase their effectiveness in the treatment and relief of the symptoms of GERD. In the presence of saliva, alginic acid reacts with sodium bicarbonate to form sodium alginate. Gastric acid causes this alginate to precipitate, forming a foaming, viscous gel that floats on the surface of the gastric contents. This provides a relatively pH-neutral barrier during episodes of acid reflux and enhances the efficacy of drugs used to treat GERD. These effects are considered to be of questionable value to the U.S. Food and Drug Administration (FDA). Alginic acid products are not indicated for the treatment of PUD.
Simethicone is a defoaming agent used to relieve gas discomfort in the stomach and intestine. It does not have antacid properties, but may be included in antacid products. Its action is to reduce the surface tension of gas bubbles in the gastrointestinal tract, which allows the gas bubbles to break up and coalesce, facilitating the elimination of the gas by belching or passing through the rectum. The FDA considers simethicone to be safe and effective as an antiflatulent agent.
Sucralfate, a complex of aluminum hydroxide and sulfated sucrose, is a cytoprotective agent that provides a physical barrier over the surface of a gastric ulcer and enhances the gastric mucosal protective system. It is employed in clinical practice to treat several gastrointestinal diseases, including PUD, GERD, and dyspepsia. After oral administration the drug disperses in the stomach and, in the presence of acid, forms a viscous suspension that binds with high affinity at the ulcer site. An adherent, physical cytoprotective barrier is produced that covers the ulcer and protects it from further attack by damaging agents such as acid, pepsin, and bile salts.
Although sucralfate has multiple actions, it possesses no meaningful antacid properties. A key element in the acute gastroprotective actions of sucralfate is its ability to maintain mucosal vascular integrity and blood flow. It enhances bicarbonate and mucus secretion, increases mucosal hydrophobicity, and induces an increase in mucosal concentration of prostaglandin—all factors considered important in tissue healing. An increase in local fibroblast growth factors and possibly other growth factors has also been proposed to explain the powerful ulcer-healing actions of sucralfate, which occur independently of a decreased gastric acid concentration in the stomach and duodenum.7
Because it is minimally absorbed from the gastrointestinal tract, sucralfate is considered a remarkably safe agent. For this reason, sucralfate is a first-choice therapy in the management of acid-related diseases during pregnancy.8 It requires an acid pH to be activated and so should not be administered concomitantly with antacids, H2 antagonists, or PPIs. The most common side effect is constipation (15%). Other reactions include dry mouth, nausea, vomiting, headache, and rashes.
Sucralfate may reduce the absorption of many other drugs, including the fluoroquinolone and tetracycline antibiotics. The use of a topical sucralfate suspension has also been advocated in the prevention or treatment of stomatitis caused by chemotherapy or radiation, despite studies that showed no substantial benefits from this drug in inhibiting radiation-induced esophagitis.21
The use of antimuscarinic drugs (muscarinic receptor antagonists) for the treatment of PUD declined dramatically after the introduction of the H2 blocker cimetidine. As discussed in Chapter 9, antimuscarinic agents (e.g., atropine) are not selective inhibitors of gastric acid secretion, and therapeutic benefits for the treatment of gastrointestinal disease accrue only at doses that cause sufficient side effects to impair patient compliance. Antimuscarinic drugs with a higher relative affinity for gastric M1 muscarinic receptors have been developed, however. Pirenzepine and telenzepine, selective M1-receptor antagonists, are currently available in other countries for the treatment of PUD, but they are still investigational in the United States. Pirenzepine and telenzepine block gastric acid secretion more selectively because the M1 receptor is not the major muscarinic receptor in most smooth muscle, cardiac muscle, or salivary glands. In those tissues, M2 and M3 muscarinic receptors predominate. Pirenzepine and telenzepine have a low incidence of side effects because of their selective inhibition of gastric acid secretion; this may make them a valuable addition to current agents used in the treatment of PUD.
Misoprostol, a synthetic prostaglandin E1 analogue, is the best studied of the prostaglandin derivatives. Although the prostaglandins are crucial in creating the alkaline mucus layer that provides cytoprotective effects on the gastroduodenal mucosa, the ulcer-healing effect of misoprostol and other prostaglandin analogues seems to be caused mainly by the inhibition of acid secretion.13 These agents interact with a basolateral receptor of the parietal cell that causes the inhibition of adenylyl cyclase. This inhibition results in reduced production of cyclic adenosine 3′,5′-monophosphate, the major second messenger for histamine-induced acid secretion. Misoprostol is approved for prevention of NSAID-induced ulcers in high-risk patients, although PPIs may be as effective and better tolerated. The most common side effects are abdominal pain (7% to 20%) and diarrhea (13% to 40%); both are dose-related. Misoprostol stimulates contraction of the uterus, which contraindicates its use during pregnancy or in women of childbearing potential. This property makes it effective, however, in women undergoing elective termination of pregnancy by facilitating expulsion of the uterine contents.
The diagnosis of GERD may be a very important finding when considering if a patient should be reclined in the dental chair. Although it is safe to place most GERD patients supine, some with severe GERD need to be kept at a 45-degree angle for their visit. Asking patients how they sleep can help elucidate what should be done. Similarly, if general anesthesia is being considered in a patient with GERD, a rapid-induction sequence with cricothyroid p/>