Gastrointestinal disorders are common in children and a wide variety of drugs are used to treat these conditions. The prevalence of gastroesophageal reflux disease (GERD) has been estimated to be as high as 8% in children (1,2). Although gastric and peptic ulcer diseases are responsible for significant morbidity and mortality in adults (3), these conditions are thought to be relatively infrequent in children (4). However, large-scale studies in children have yet to be performed, and the true prevalence and economic impact of pediatric ulcer disease is unknown (5). “Stress gastritis” is being increasingly recognized in children and adolescents and the most serious cases are typically secondary to Helicobacter pylori infection, which requires combination therapy to eradicate (6). Stress gastritis commonly occurs in critically ill hospitalized patients, including children, and many children are presumptively treated for the condition (7,8,9).

Children are commonly referred to as “therapeutic orphans” to reflect the relative disproportion of drug studies performed in pediatric as opposed to adult populations. Although this term was coined more than 40 years ago, it remains relevant today. Although progress has occurred in the last 15 years and an increased number of drugs have received Food and Drug Administration (FDA) approval for pediatric indications, many drugs commonly used to treat gastrointestinal conditions in children have not been thoroughly studied. This is especially true of off-patent drugs. Significant knowledge gaps remain in the pharmacology of these drugs in children, particularly for children younger than 1 year. This chapter reviews the current pediatric knowledge of drugs utilized to treat the more common pediatric gastrointestinal disorders. When available, the specific pharmacokinetics and pharmacodynamics of these drugs in children are discussed.

Nausea and vomiting occur in a wide variety of diseases and clinical settings. Vomiting is controlled by the vomiting center of the medulla and has input from at least four sources, the chemoreceptor trigger zone, the cortex, the vestibular apparatus, and the gastrointestinal tract (10,11). These pathways are mediated by various neurotransmitters including serotonin (5-HT), which acts through central and peripheral 5-HT₃ receptors (12). Various clinical factors, such as the emetogenic potential of chemotherapeutic drugs or the etiology of vomiting, determine the efficacy of antiemetics. Because multiple neurotransmitters are involved in vomiting, a number of agents from various drug classes have been used to treat vomiting, including muscarinic agents, cannabinoids, steroids, and antagonists of histamine, dopamine, and serotonin receptors (10).

The dopamine antagonists (metoclopramide and the phenothiazines) and the 5-HT₃-receptor antagonists (ondansetron) are commonly used antiemetics (11,12,13). Metoclopramide blocks central dopamine receptors in the chemoreceptor trigger zone (13). Promethazine is a phenothiazine derivative with histamine H₁-receptor antagonist and anticholinergic properties. The 5-HT₃ antagonists block 5-HT₃ receptors in the enterochromaffin cells of the intestinal mucosa, thereby decreasing vagal input to the vomiting center, although these agents may also block receptors in the central nervous system (10,11,12). The high degree of receptor specificity of the 5-HT₃-receptor antagonists is associated with high efficacy and relatively fewer adverse effects of these drugs (14), compared with other agents used for this indication.

The 5-HT₃ antagonists are used for the management of anesthesia-, chemotherapy-, and radiation-related nausea and vomiting (12,15,16). Of the available drugs in this class, ondansetron has received the most study in children. The 5-HT₃ antagonists are generally viewed to be as effective as, or superior to, antidopaminergic drugs, and their efficacy is further enhanced by the adjunctive use of dexamethasone (12,15,16,17). Ondansetron’s efficacy for the treatment of chemotherapy-related nausea and vomiting in children appears to vary by age and emetogenicity of the chemotherapeutic regimen. Younger children were shown to have better response rates in a survey study (18). In the setting of gastroenteritis, ondansetron was found to be superior to placebo or metoclopramide (19,20) or dexamethasone (21) in the management of vomiting associated with acute gastroenteritis (19,20,21,22,23). Ondansetron is also effective in children with gastroenteritis who fail oral rehydration therapy (22) and its use may reduce the length of stay in
the emergency department (23). In addition, ondansetron given prior to ketamine for procedural sedation reduced vomiting rates in children (24). Granisetron is also approved for use in children with chemotherapy-related and postoperative nausea and vomiting (25,26).

Despite the efficacy of ondansetron in the setting of gastroenteritis, its use does not appear to be widespread. A review of antiemetic use in industrialized nations showed that up to 23% of children with gastroenteritis receive prescriptions for antiemetics. The most common drugs prescribed included promethazine, dimenhydrinate, diphenhydramine, and domperidone and prescription patterns varied by country. Promethazine was most commonly prescribed in the United States, and ondansetron compromised only 3% of prescriptions for this condition (27).

Other 5-HT₃ antagonists include dolasetron, granisetron, tropisetron, ramosetron, and palonosetron. In adults, the elimination half-lives for these compounds range from 3.9 to 10.6 hours (28). Of these compounds, palonosetron has the longest elimination rate; it has a half-life of up to 60 to 80 hours in adults, allowing for once-daily dosing and prolonged efficacy of up to 7 days (29). All drugs in this class are metabolized by CYPP450. Tropisetron and dolasetron are primarily metabolized by CYP2D6, and granisetron is primarily metabolized by CYP3A4. Ondansetron is metabolized by CYP2D6, CYP2E1, CYP3A, and CYP1A2 (28). The role of genetic variability in CYP2D6 activity has been examined as a determinant of drug efficacy (30,31). Approximately 5% to 10% of Caucasians are poor metabolizers (PMs) for CYP2D6, while 2% are considered ultrarapid metabolizers. Other ethnic populations have higher percentages of ultra rapid metabolizers. The efficacy of tropisetron and ondansetron was compared between ultra rapid and poor metabolizers for CYP2D6 in an oncology setting. Ultra rapid metabolizers were shown to have reduced control of nausea and vomiting compared with poor metabolizers following treatment with tropisetron; this effect was similar but less pronounced with ondansetron (32). These data suggest that a personalized medicine approach may be appropriate and feasible in the clinical setting of chemotherapy-induced nausea and vomiting (28).

Common adverse effects associated with ondansetron and other 5-HT₃ antagonists include anxiety, drowsiness, headache, constipation, and diarrhea (14). In addition, 5-HT₃ drugs have the potential to block either cardiac sodium or potassium channels, resulting in prolongation of the QRS or QTc intervals, respectively. Prescribing information for dolasetron and tropisetron contain warnings related to this potential cardiac toxicity (28). Granisetron altered cardiac conduction intervals in children receiving chemotherapy, but these events were asymptomatic (33). Buyukavci examined the effect of ondansetron (0.1 mg per kg infusion) versus granisetron (40 μg per kg infusion) on the electrocardiogram (ECG) and heart rate in children (n = 22) receiving antiemetics as prophylaxis during high-dose treatment with methotrexate (34). A decrease in heart rate at 1 and 3 hours and significant prolongation of mean QT and QTc dispersions at 1 hour after infusion were noted for granisetron. However, it should be noted that patients with these findings were asymptomatic. In contrast, no ECG or heart rate changes were noted in patients that received ondansetron. Similar findings have been reported for adults, although some case reports demonstrate increased symptomatology in select patients (35,36). It is recommended that 5-HT₃ receptor antagonists not be used in combination with drugs that have the potential to prolong QRS or QTc intervals. Concomitant use of 5-HT₃ antagonists that are highly metabolized by CYP2D6 (e.g., dolasetron, tropisetron) with drugs such as that inhibit CYP2D6 (e.g., fluoxetine, paroxetine, quinidine, or haloperidol) have the potential to cause drug interactions and possible adverse events (28). Limited pediatric data exist for the newer drugs in this class.

Pediatric dose-ranging studies of ondansetron for the management of postoperative nausea and vomiting have used doses of 0.05 to 0.2 mg per kg (37,38,39,40,41,42,43,44,45). Khalil (46) showed in a prospective, randomized, double-blind, placebo-controlled study that intravenous ondansetron (0.1 mg per kg) was safe and effective in the prevention of postoperative emesis in 1- to 24-month-old pediatric patients undergoing elective surgery under general anesthesia. In general, higher doses of ondansetron appear to have greater efficacy, although doses of 0.05 mg per kg are effective in many patients (37,38,39). Similar doses are frequently used to treat chemotherapy-related emesis with a titration to clinical effect (12). For treatment of vomiting-associated gastroenteritis, unit doses of 2 mg, 4 mg, and 8 mg have been used in children weighing 8 to 15 kg, 16 to 29 kg, and more than 29 kg, respectively (23). A single dose of drug is thought to be sufficient for the treatment of gastroenteritis (22). Although ondansetron is expensive, its use in this setting may avoid the need for hospitalization for intravenous hydration, especially when oral rehydration is possible.

The pharmacokinetic profile of ondansetron in children does not differ substantially from that of adults (12). The terminal elimination half-life in younger children (3 to 12 years), adolescents, and adults varies between 2.5 and 4 hours, being slightly less in younger children (12). Similarly, there are minor variations in the volume of distribution, area under the concentration versus time curve, and clearance. The 5-HT₃ antagonists are generally well absorbed (60%), although ondansetron undergoes a significant first-pass effect. Significant hepatic insufficiency may prolong the elimination of ondansetron, but toxicity has not been reported in this setting (17). Enzyme-inducing agents may enhance the elimination of ondansetron, but no toxicities secondary to drug interactions have been reported (12).

Antacids are used in children for the treatment of gastritis, esophagitis, peptic ulcer disease, and GERD (41,42). In addition, they are included in combination treatment regimens for the management of H. pylori-related disease (42). In the past, antacids were used as prophylaxis for stress ulceration in intensive care units (8) and prior to surgical procedures. In recent years, antacids have been largely replaced by other acid-modifying drugs [e.g., H₂-receptor antagonists, proton pump inhibitors (PPIs)] due to safety and dosing concerns. Antacids are considered appropriate for use as short-term therapies (<2 weeks) for dyspepsia.

Antacids reduce and neutralize secreted gastric acid and have cytoprotective effects. Data from adult studies show that antacids at the proper doses are effective in the treatment of ulcer disease (42) and stress ulcer prophylaxis (43). Sucralfate, ranitidine, and almagate were equally effective as prophylaxis for gastrointestinal hemorrhage in critically ill children (8).

Sodium bicarbonate and calcium carbonate are the most potent antacids, followed by magnesium- and then aluminum-containing products. Sodium bicarbonate and calcium carbonate are also rapid-acting antacids. Chronic use of sodium bicarbonate is associated with fluid retention, systemic alkalosis, and the milk alkali syndrome. Calcium carbonate has a longer duration of action than sodium bicarbonate and has also been associated with hypercalcemia, hypercalciuria, renal calcium deposits, compromised renal function, and gastric acid hypersecretion (44,45). Diarrhea and hypermagnesemia are associated with the use of magnesium-containing antacids, particularly in patients with compromised renal function. Adverse events associated with the use of aluminum-containing antacids include constipation, hypophosphatemia, and hypocalcemia. Aluminum accumulation and the formation of bezoars have also been reported for aluminum-containing antacids, particularly in young infants with compromised renal function (41,47).

Concomitant use of other drugs with antacids may decrease drug absorption, and alteration of gastric pH may change the dissolution rate of drugs. Dosing of antacids 2 hours after other drugs (e.g., quinolones, H₂-receptor antagonists) may help to avoid this drug interaction (48). In general, the smallest effective dose of antacid should be utilized in children, beginning at 0.5 to 1.0 mL per kg in infants and 5 to 10 mL in children, up to a single dose of 10 to 20 mL. Administration of antacids 1 hour after meals has been shown to be effective in reducing gastric acidity in infants and to allow for reduction of the antacid dose (49). Long-term therapy (>2 to 4 weeks) with antacids in infants and children should be closely monitored for adverse effects.

Prokinetic agents are utilized to improve gastric hypomotility, a frequent component of many pediatric gastrointestinal disorders (50). GER is the most common disorder of gastric motility in children and infants, and approximately 50% of mothers report that their infants regurgitate two or more times per day (50,51). For the majority of infants, GER is a self-limited, transient problem that resolves by 8 to 12 months of age and can be managed with nonpharmacologic therapies (51). However, pharmacotherapy may be indicated in children with pathologic GER (e.g., poor weight gain, Sandifer syndrome, esophagitis, esophageal stricture, aspiration, and airway inflammation). Surgical management is typically reserved for patients who fail therapy with acid-reducing drugs and prokinetic agents (51).

Transient relaxation of the lower esophageal sphincter is considered one of the most important factors in the pathogenesis of GER. Delayed gastric emptying is also a factor and is noted in approximately one-half of patients with GER (51). Bethanechol, metoclopramide, and erythromycin improve lower esophageal sphincter tone, and metoclopramide and erythromycin, but not bethanechol, improve gastric emptying. However, with the withdrawal of cisapride (discussed later) and the adverse effects associated with metoclopramide, other prokinetic agents, such as erythromycin, are more commonly used.

Feeding intolerance in premature newborns is another common clinical problem in pediatrics. Migrating motor complexes are responsible for phasic contractions that move distally through the intestine. These complexes appear, at least in part, to be stimulated by increased activity of the receptor for motilin, a polypeptide hormone (52,53). Infants begin to express increased numbers of motilin receptors at approximately 32 weeks of gestational age (53). Enteral feeding may result in increased release of enteric polypeptide hormones (50). Thus, prokinetic drugs that stimulate motilin receptor activity may result in improved tolerance of feeding in premature newborns. Currently, motilin receptor agonists are undergoing safety and efficacy testing in early phase clinical trials in adults with impaired gastric motor function (54,55,56).