Pharmacology_Katzung

Pharmacology_Katzung. TABLE 62–1 Clinical comparisons of H2-receptor blockers. bid, twice daily; HS, bedtime. The H2 antagonists exhibit competitive inhibition at the parietal cell H2 receptor and suppress basal and meal-stimulated acid secretion (Figure 62–2) in a linear, dose-dependent manner. They are highly selective and do not affect H1 or H3 receptors (see Chapter 16). The volume of gastric secretion and the concentration of pepsin are also reduced. H2 antagonists reduce acid secretion stimulated by histamine as well as by gastrin and cholinomimetic agents through two mechanisms. First, histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H2 receptor. Second, direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of H2-receptor blockade.


Pharmacology_Katzung

Pharmacology_Katzung. The potencies of the four H2-receptor antagonists vary over a 50-fold range (Table 62–1). When given in usual prescription doses, however, all inhibit 60–70% of total 24-hour acid secretion. H2 antagonists are especially effective at inhibiting nocturnal acid secretion (which depends largely on histamine), but they have a modest impact on meal-stimulated acid secretion (which is stimulated by gastrin and acetylcholine as well as histamine). Therefore, nocturnal and fasting intragastric pH is raised to 4–5, but the impact on the daytime, meal-stimulated pH profile is less. Recommended prescription doses maintain greater than 50% acid inhibition for 10 hours; hence, these drugs are commonly given twice daily. At doses available in over-the-counter formulations, the duration of acid inhibition is 6–10 hours.


Pharmacology_Katzung

Pharmacology_Katzung. H2-receptor antagonists continue to be prescribed, but PPIs (see below) are more commonly prescribed than H2 antagonists for most clinical indications. The over-the-counter preparations of the H2 antagonists are heavily used by the public. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Gastroesophageal reflux disease (GERD)—Patients with infrequent heartburn or dyspepsia (fewer than three times per week) may take either antacids or intermittent H2 antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H2 antagonists. However, the effect of antacids is short-lived (1–2 hours) compared with H2 antagonists (6–10 hours). H2 antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice-daily H2 antagonists (Table 62–1) or PPIs. In patients with erosive esophagitis (approximately 50% of patients with GERD), H2 antagonists afford healing in less than 50% of patients; hence PPIs are preferred because of their superior acid inhibition. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Peptic ulcer disease—PPIs have largely replaced H2 antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H2 antagonists are still sometimes used. Nocturnal acid suppression by H2 antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime, resulting in ulcer healing rates >80–90% after 6–8 weeks of therapy. 0 0900 1200 1500 1800 2100 0600 0800 hours Time of day


Pharmacology_Katzung

Pharmacology_Katzung. 0 0900 1200 1500 1800 2100 0600 0800 hours Time of day FIGURE 62–2 Twenty-four-hour median intragastric acidity pretreatment (red) and after 1 month of treatment with either ranitidine, 150 mg twice daily (blue, H2 block), or omeprazole, 20 mg once daily (green, PPI). Note that H2-receptor antagonists have a marked effect on nocturnal acid secretion but only a modest effect on meal-stimulated secretion. Proton-pump inhibitors (PPIs) markedly suppress meal-stimulated and nocturnal acid secretion. (Data from Lanzon-Miller S et al: Twenty-four-hour intragastric acidity and plasma gastrin concentration before and during treatment with either ranitidine or omeprazole. Aliment Pharmacol Ther 1987;1:239.)


Pharmacology_Katzung

Pharmacology_Katzung. For patients with ulcers caused by aspirin or other NSAIDs, the NSAID should be discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a PPI should be given instead of an H2 antagonist to more reliably promote ulcer healing. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. H pylori should be treated with a 10to 14-day course of therapy including a PPI and two or three antibiotics (see below). 3. Nonulcer dyspepsia—H2 antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated. 4. Prevention of bleeding from stress-related gastritis—


Pharmacology_Katzung

Pharmacology_Katzung. 4. Prevention of bleeding from stress-related gastritis— Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1–5% of critically ill patients as a result of impaired mucosal defense mechanisms caused by poor perfusion. Although most critically ill patients have normal or decreased acid secretion, numerous studies have shown that agents that increase intragastric pH (H2 antagonists or PPIs) reduce the incidence of clinically significant bleeding and should be administered to patients who are at high risk of gastrointestinal bleeding. However, the optimal agent is uncertain. For patients who are unable to receive enteral medications, either intravenous H2 antagonists or PPIs may be administered. Continuous infusions of H2 antagonists are generally preferred to bolus infusions because they achieve more consistent, sustained elevation of intragastric pH.


Pharmacology_Katzung

Pharmacology_Katzung. H2 antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation. Some studies suggest that intravenous H2 antagonists (or PPIs) may increase the risk of nosocomial pneumonia in critically ill patients. Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H2 antagonists, especially in patients in the intensive care unit who are elderly or who have renal or hepatic dysfunction. These events may be more common with cimetidine. Mental status changes rarely occur in ambulatory patients. Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H2 antagonists.


Pharmacology_Katzung

Pharmacology_Katzung. Although there are no known harmful effects on the fetus, H2 antagonists cross the placenta. Therefore, they should not be administered to pregnant women unless absolutely necessary. The H2 antagonists are secreted into breast milk and may therefore affect nursing infants. H2 antagonists may rarely cause blood dyscrasias. Blockade of cardiac H2 receptors may cause bradycardia, but this is rarely of clinical significance. Rapid intravenous infusion may cause Drugs Used in the Treatment of Gastrointestinal Diseases 1091 bradycardia and hypotension through blockade of cardiac H2 receptors; therefore, intravenous infusions should be given over 30 minutes. H2 antagonists rarely cause reversible abnormalities in liver chemistry.


Pharmacology_Katzung

Pharmacology_Katzung. Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4). Hence, the half-lives of drugs metabolized by these pathways may be prolonged. Ranitidine binds 4–10 times less avidly than cimetidine to cytochrome P450. Negligible CYP interaction occurs with nizatidine and famotidine. H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels. Since their introduction in the late 1980s, these efficacious acid inhibitory agents have assumed the major role for the treatment of acid-peptic disorders. PPIs are now among the most widely prescribed drugs worldwide.


Pharmacology_Katzung

Pharmacology_Katzung. Six PPIs are available for clinical use: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, and pantoprazole. All are substituted benzimidazoles that resemble H2 antagonists in structure (Figure 62–3) but have a completely different mechanism of action. Omeprazole and lansoprazole are racemic mixtures of Rand S-isomers. Esomeprazole is the S-isomer of omeprazole and dexlansoprazole the R-isomer of lansoprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations (Table 62–2).


Pharmacology_Katzung

Pharmacology_Katzung. PPIs are administered as inactive prodrugs. To protect the acid-labile prodrug from rapid destruction within the gastric lumen, oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. For children or patients with dysphagia or enteral feeding tubes, capsule formulations (but not tablets) may be opened and the microgranules mixed with apple or orange juice or mixed with soft foods (eg, applesauce). Esomeprazole, omeprazole, and pantoprazole are also available as oral suspensions. Lansoprazole is available as a tablet formulation that disintegrates in the mouth, and rabeprazole is available in a formulation that may be sprinkled on food. Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100–1680 mg NaHCO3; 304–460 mg of sodium) to protect the naked


Pharmacology_Katzung

Pharmacology_Katzung. may be sprinkled on food. Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100–1680 mg NaHCO3; 304–460 mg of sodium) to protect the naked (non-enteric-coated) drug from acid degradation. When administered on an empty stomach by


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 62–3 Molecular structure of the proton-pump inhibitors: omeprazole, lansoprazole, pantoprazole, and the sodium salt of rabeprazole. Omeprazole and esomeprazole have the same chemical structure (see text). mouth or enteral tube, this “immediate-release” suspension results in rapid omeprazole absorption (Tmax < 30 minutes) and onset of acid inhibition. The PPIs are lipophilic weak bases (pKa 4–5) and, after intestinal absorption, diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H+/K+-ATPase, irreversibly inactivating the enzyme.


Pharmacology_Katzung

Pharmacology_Katzung. The pharmacokinetics of available PPIs are shown in Table 62–2. Immediate-release omeprazole has a faster onset of acid inhibition than other oral formulations. Although differences in pharmacokinetic profiles may affect speed of onset and duration of acid inhibition in the first few days of therapy, they are of little clinical importance with continued daily administration.


Pharmacology_Katzung

Pharmacology_Katzung. The bioavailability of all agents is decreased approximately 50% by food; hence, the drugs should be administered on an empty stomach. In a fasting state, only 10% of proton pumps are actively secreting acid and susceptible to inhibition. PPIs should be administered approximately 1 hour before a meal (usually breakfast), so that the peak serum concentration coincides with the maximal activity of proton-pump secretion. The drugs have a short serum half-life of about 1.5 hours, but acid inhibition lasts up to 24 hours owing to the irreversible inactivation of the proton pump. At least 18 hours are required for synthesis of new H+/K+-ATPase pump molecules. Because not all proton pumps are inactivated with the first dose of medication, up to 3–4 days of daily medication are required before the full acid-inhibiting potential is reached. Similarly, after stopping the drug, it takes 3–4 days for full acid secretion to return.


Pharmacology_Katzung

Pharmacology_Katzung. PPIs undergo rapid first-pass and systemic hepatic metabolism and have negligible renal clearance. Dose reduction is not needed for patients with renal insufficiency or mild to moderate TABLE 62–2 Pharmacokinetics of proton pump inhibitors. Rabeprazole 5 52 1.0–2.0 3.1 20 mg qd GERD, gastroesophageal reflux disease; NA, data not available. liver disease but should be considered in patients with severe liver impairment. Although other proton pumps exist in the body, the H+/K+-ATPase appears to exist only in the parietal cell and is distinct structurally and functionally from other H+-transporting enzymes.


Pharmacology_Katzung

Pharmacology_Katzung. The intravenous formulations of esomeprazole and pantoprazole have characteristics similar to those of the oral drugs. When given to a fasting patient, they inactivate acid pumps that are actively secreting, but they have no effect on pumps in quiescent, nonsecreting vesicles. Because the half-life of a single injection of the intravenous formulation is short, acid secretion returns several hours later as pumps move from the tubulovesicles to the canalicular surface. Thus, to provide maximal inhibition during the first 24–48 hours of treatment, the intravenous formulations must be given as a continuous infusion or as repeated bolus injections. The optimal dosing of intravenous PPIs to achieve maximal blockade in fasting patients is not yet established. From a pharmacokinetic perspective, PPIs are ideal drugs: they have a short serum half-life, they are concentrated and activated near their site of action, and they have a long duration of action.


Pharmacology_Katzung

Pharmacology_Katzung. In contrast to H2 antagonists, PPIs inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, the proton pump. In standard doses, PPIs inhibit 90–98% of 24-hour acid secretion (Figure 62–2). When administered at equivalent doses, the different agents show little difference in clinical efficacy. In a crossover study of patients receiving long-term therapy with five PPIs, the mean 24-hour intragastric pH varied from 3.3 (pantoprazole, 40 mg) to 4.0 (esomeprazole, 40 mg), and the mean number of hours the pH was higher than 4 varied from 10.1 (pantoprazole, 40 mg) to 14.0 (esomeprazole, 40 mg). Although dexlansoprazole has a delayed-release formulation that results in a longer Tmax and greater AUC than other PPIs, it appears comparable to other agents in the ability to suppress acid secretion. This is because acid suppression is more dependent upon irreversible inactivation of the proton pump than the pharmacokinetics of different


Pharmacology_Katzung

Pharmacology_Katzung. to other agents in the ability to suppress acid secretion. This is because acid suppression is more dependent upon irreversible inactivation of the proton pump than the pharmacokinetics of different agents.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Gastroesophageal reflux disease—PPIs are the most effective agents for the treatment of erosive reflux disease, esophageal complications of reflux disease (peptic stricture or Barrett’s esophagus), and extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and tissue healing in 85–90% of patients; up to 15% of patients require twice-daily dosing. GERD symptoms recur in over 80% of patients within 6 months after discontinuation of a PPI. For patients with erosive esophagitis or esophageal complications, long-term daily maintenance therapy with a full-dose or half-dose PPI is usually needed. Many patients with nonerosive GERD may be treated successfully with intermittent courses of PPIs or H2 antagonists taken as needed (“on demand”) for recurrent symptoms. Drugs Used in the Treatment of Gastrointestinal Diseases 1093


Pharmacology_Katzung

Pharmacology_Katzung. Drugs Used in the Treatment of Gastrointestinal Diseases 1093 In current clinical practice, many patients with symptomatic GERD are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. Empiric treatment with PPIs provides sustained symptomatic relief in 70–80% of patients, compared with 50–60% with H2 antagonists. Because of recent cost reductions, PPIs are used increasingly as first-line therapy for patients with symptomatic GERD. Due to recent safety concerns, however, initial empiric treatment with an H2 antagonist should be considered. Sustained acid suppression with twice-daily PPIs for at least 3 months is used to treat extraesophageal complications of reflux disease (asthma, chronic cough, laryngitis, and noncardiac chest pain).


Pharmacology_Katzung

Pharmacology_Katzung. 2. Peptic ulcer disease—Compared with H2 antagonists, PPIs afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers. All the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6–8 weeks. a.


Pharmacology_Katzung

Pharmacology_Katzung. H pylori-associated ulcers—For H pylori-associated ulcers, there are two therapeutic goals: to heal the ulcer and to eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a PPI. PPIs promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and—by raising intragastric pH—lowering the minimal inhibitory concentrations of antibiotics against H pylori. Until recently, the most commonly recommended treatment regimen consisted of a 14-day regimen of “triple therapy”: a PPI twice daily; clarithromycin, 500 mg twice daily; and either amoxicillin, 1 g twice daily, or metronidazole, 500 mg twice daily. Due to increasing treatment failures attributable to rising clarithromycin resistance, “quadruple therapy” is now recommended as first-line treatment for patients who likely have clarithromycin resistance due to prior exposure or to residence in regions with high clarithromycin resistance.


Pharmacology_Katzung

Pharmacology_Katzung. therapy” is now recommended as first-line treatment for patients who likely have clarithromycin resistance due to prior exposure or to residence in regions with high clarithromycin resistance. Two 14-day treatment regimens currently are recommended. Each includes a PPI twice daily with either: (a) bismuth subsalicylate 524 mg, metronidazole 500 mg, and tetracycline 500 mg, all given four times daily; or (b) amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily. After completion of antibiotic therapy, the PPI should be continued once daily for a total of 4–6 weeks to ensure complete ulcer healing.


Pharmacology_Katzung

Pharmacology_Katzung. b. NSAID-associated ulcers—For patients with ulcers caused by aspirin or other NSAIDs, either H2 antagonists or PPIs provide rapid ulcer healing so long as the NSAID is discontinued; however, continued use of the NSAID impairs ulcer healing. In patients with NSAID-induced ulcers who require continued NSAID therapy, treatment with a PPI more reliably promotes ulcer healing. Asymptomatic peptic ulceration develops in 10–20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1–2% of persons per year. PPIs taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs.


Pharmacology_Katzung

Pharmacology_Katzung. c. Prevention of rebleeding from peptic ulcers—In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of rebleeding from ulcers that have a visible vessel or adherent clot is increased. Rebleeding of this subset of high-risk ulcers is reduced significantly with PPIs administered for 3–5 days either as high-dose oral therapy (eg, omeprazole, 40 mg orally twice daily) or as a continuous intravenous infusion. It is believed that an intragastric pH higher than 6 may enhance coagulation and platelet aggregation. The optimal dose of intravenous PPI needed to achieve and maintain this level of near-complete acid inhibition is unknown; however, initial bolus administration of esomeprazole or pantoprazole (80 mg) followed by constant infusion (8 mg/h) is commonly recommended. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Nonulcer dyspepsia—PPIs have modest efficacy for treatment of nonulcer dyspepsia, benefiting 10–20% more patients than placebo. Despite their use for this indication, superiority to H2 antagonists (or even placebo) has not been conclusively demonstrated. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Prevention of stress-related mucosal bleeding—As discussed previously (see H2-Receptor Antagonists), PPIs (given orally, by nasogastric tube, or by intravenous infusions) may be administered to reduce the risk of clinically significant stress-related mucosal bleeding in critically ill patients. The only PPI approved by the US Food and Drug Administration (FDA) for this indication is an oral immediate-release omeprazole formulation, which is administered by nasogastric tube twice daily on the first day, then once daily. Although not FDA approved for this indication, other PPI suspension formulations (esomeprazole, omeprazole, pantoprazole) may also be used. For patients with nasoenteric tubes, PPI suspensions may be preferred to intravenous H2 antagonists or PPIs because of comparable efficacy, lower cost, and ease of administration.


Pharmacology_Katzung

Pharmacology_Katzung. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferred to intravenous PPIs because of their proven efficacy. Although PPIs are increasingly used, there are no controlled trials demonstrating efficacy or optimal dosing. 5. Gastrinoma and other hypersecretory conditions— Patients with isolated gastrinomas are best treated with surgical resection. In patients with metastatic or unresectable gastrinomas, massive acid hypersecretion results in peptic ulceration, erosive esophagitis, and malabsorption. With PPIs, excellent acid suppression can be achieved in all patients. Dosage is titrated to reduce basal acid output to less than 5–10 mEq/h. Typical doses of omeprazole are 60–120 mg/d.


Pharmacology_Katzung

Pharmacology_Katzung. 1. General—Although PPIs have been considered to be extremely safe, a number of recent safety concerns have been raised. As with most drugs, PPIs should be prescribed at the lowest effective dose and the risks versus benefits of long-term use carefully weighed. Diarrhea, headache, and abdominal pain are reported in 1–5% of patients, although the frequency of these events is only slightly increased compared with placebo. In large observational studies, PPIs have been associated with an increased risk of acute interstitial nephritis and chronic kidney disease compared to nonusers or users of H2-receptor antagonists. A mechanism by which kidney damage might occur has not been determined. Some epidemiologic studies have also detected an increased risk of dementia in long-term PPI users, although causality has not been established. PPIs are not teratogenic in animal models; however, safety during pregnancy has not been established. 2.


Pharmacology_Katzung

Pharmacology_Katzung. Nutrition—Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton-pump inhibition, potentially leading to subnormal B12 levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (non-heme iron, insoluble calcium salts, magnesium). Meta-analyses of cohort and case-control studies have detected a modest increase in the risk of hip fracture in patients taking long-term PPIs. Although a causal relationship is unproven, PPIs may reduce calcium absorption or inhibit osteoclast function. All PPIs carry an FDA-mandated warning of a possible increased risk of hip, spine, and wrist fractures. Patients who require long-term PPIs—especially those with risk factors for osteoporosis—should have monitoring of bone density and should be provided calcium supplements. Cases of severe, life-threatening hypomagnesemia with secondary hypocalcemia due to PPIs have been reported, possibly due to decreased


Pharmacology_Katzung

Pharmacology_Katzung. of bone density and should be provided calcium supplements. Cases of severe, life-threatening hypomagnesemia with secondary hypocalcemia due to PPIs have been reported, possibly due to decreased intestinal absorption.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Respiratory and enteric infections—Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Increases in gastric bacterial concentrations are detected in patients taking PPIs, which is of unknown clinical significance. Some studies have reported an increased risk of both community-acquired respiratory infections and nosocomial pneumonia among patients taking PPIs. There is a twoto threefold increased risk for hospitaland community-acquired Clostridium difficile infection in patients taking PPIs. There also is a small increased risk of other enteric infections (eg, Salmonella, Shigella, Escherichia coli, Campylobacter), which should be considered particularly when traveling in underdeveloped countries. 4. Potential problems due to increased serum gastrin—


Pharmacology_Katzung

Pharmacology_Katzung. Gastrin levels are regulated by intragastric acidity. Acid suppression alters normal feedback inhibition so that median serum gastrin levels rise 1.5to twofold in patients taking PPIs. Although gastrin levels remain within normal limits in most patients, they exceed 500 pg/mL (normal, <100 pg/mL) in 3%. Upon stopping the drug, the levels normalize within 4 weeks. The rise in serum gastrin levels may stimulate hyperplasia of ECL and parietal cells, which may cause transient rebound acid hypersecretion with increased dyspepsia or heartburn after drug discontinuation, which abate within 2–4 weeks after gastrin and acid secretion normalize. In female rats given PPIs for prolonged periods, hypergastrinemia caused gastric carcinoid tumors that developed in areas of ECL hyperplasia. Although humans who take PPIs for a long time also may exhibit ECL hyperplasia, carcinoid tumor formation has not been documented. At present, routine monitoring of serum gastrin levels is not recommended in


Pharmacology_Katzung

Pharmacology_Katzung. humans who take PPIs for a long time also may exhibit ECL hyperplasia, carcinoid tumor formation has not been documented. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged PPI therapy.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Other potential problems due to decreased gastric acidity—Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasia—known risk factors for gastric adenocarcinoma. A special FDA Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged PPI therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is not recommended in patients who require long-term PPI therapy. Longterm PPI therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients, which may disappear after stopping the drug and are of uncertain clinical


Pharmacology_Katzung

Pharmacology_Katzung. PPI therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients, which may disappear after stopping the drug and are of uncertain clinical significance.


Pharmacology_Katzung

Pharmacology_Katzung. Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability, eg, ketoconazole, itraconazole, digoxin, and atazanavir. All PPIs are metabolized by hepatic P450 cytochromes, including CYP2C19 and CYP3A4. Because of the short half-lives of PPIs, clinically significant drug interactions are rare. Omeprazole may inhibit the metabolism of clopidogrel, warfarin, diazepam, and phenytoin. Esomeprazole also may decrease metabolism of diazepam. Lansoprazole may enhance clearance of theophylline. Rabeprazole and pantoprazole have no significant drug interactions.


Pharmacology_Katzung

Pharmacology_Katzung. The FDA has issued a warning about a potentially important adverse interaction between clopidogrel and PPIs. Clopidogrel is a prodrug that requires activation by the hepatic P450 CYP2C19 isoenzyme, which also is involved to varying degrees in the metabolism of PPIs (especially omeprazole, esomeprazole, lansoprazole, and dexlansoprazole). Thus, PPIs could reduce clopidogrel activation (and its antiplatelet action) in some patients. Several large retrospective studies have reported an increased incidence of serious cardiovascular events in patients taking clopidogrel and a PPI. In contrast, three smaller prospective randomized trials have not detected an increased risk. When PPIs are prescribed to patients taking clopidogrel, agents with minimal CYP2C19 inhibition (pantoprazole or rabeprazole) may be preferred.


Pharmacology_Katzung

Pharmacology_Katzung. The gastroduodenal mucosa has evolved a number of defense mechanisms to protect itself against the noxious effects of acid and pepsin. Both mucus and epithelial cell-cell tight junctions restrict back diffusion of acid and pepsin. Epithelial bicarbonate secretion establishes a pH gradient within the mucous layer in which the pH ranges from 7 at the mucosal surface to 1–2 in the gastric lumen. Blood flow carries bicarbonate and vital nutrients to surface cells. Areas of injured epithelium are quickly repaired by restitution, a process in which migration of cells from gland neck cells seals small erosions to reestablish intact epithelium. Mucosal prostaglandins appear to be important in stimulating mucus and bicarbonate secretion and mucosal blood flow. A number of agents that potentiate these mucosal defense mechanisms are available for the prevention and treatment of acid-peptic disorders.


Pharmacology_Katzung

Pharmacology_Katzung. Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide. In water or acidic solutions it forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hours. Sucralfate has limited solubility, breaking down into sucrose sulfate (strongly negatively charged) and an aluminum salt. Less than 3% of intact drug and aluminum is absorbed from the intestinal tract; the remainder is excreted in the feces. A variety of beneficial effects have been attributed to sucralfate, but the precise mechanism of action is unclear. It is believed that the negatively charged sucrose sulfate binds to positively charged proteins in the base of ulcers or erosion, forming a physical barrier that restricts further caustic damage and stimulates mucosal prostaglandin and bicarbonate secretion.


Pharmacology_Katzung

Pharmacology_Katzung. Sucralfate is administered in a dosage of 1 g four times daily on an empty stomach (at least 1 hour before meals). At present, its clinical uses are limited. Sucralfate (administered as a slurry through a nasogastric tube) reduces the incidence of clinically significant upper gastrointestinal bleeding in critically ill patients hospitalized in the intensive care unit, although it is slightly less effective than intravenous H2 antagonists. Sucralfate is still used by many clinicians for prevention of stress-related bleeding because of concerns that acid inhibitory therapies (antacids, H2 antagonists, and PPIs) may increase the risk of nosocomial pneumonia. Because it is not absorbed, sucralfate is virtually devoid of systemic adverse effects. Constipation occurs in 2% of patients due to the aluminum salt. Because a small amount of aluminum is absorbed, it should not be used for prolonged periods in patients with renal insufficiency.


Pharmacology_Katzung

Pharmacology_Katzung. Sucralfate may bind to other medications, impairing their absorption. The human gastrointestinal mucosa synthesizes a number of prostaglandins (see Chapter 18); the primary ones are prostaglandins E and F. Misoprostol, a methyl analog of PGE1, has been approved for gastrointestinal conditions. After oral administration, it is rapidly absorbed and metabolized to a metabolically active free acid. The serum half-life is less than 30 minutes; hence, it must be administered 3–4 times daily. It is excreted in the urine; however, dose reduction is not needed in patients with renal insufficiency.


Pharmacology_Katzung

Pharmacology_Katzung. Misoprostol has both acid inhibitory and mucosal protective properties. It is believed to stimulate mucus and bicarbonate secretion and enhance mucosal blood flow. Misoprostol can reduce the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%. It is approved for prevention of NSAID-induced ulcers in high-risk patients; however, misoprostol has never achieved widespread use owing to its high adverse-effect profile and need for multiple daily dosing.


Pharmacology_Katzung

Pharmacology_Katzung. Two bismuth compounds are available: bismuth subsalicylate, a nonprescription formulation containing bismuth and salicylate, and bismuth subcitrate potassium. In the USA, bismuth subcitrate is available only as a combination prescription product that also contains metronidazole and tetracycline for the treatment of H pylori. Bismuth subsalicylate undergoes rapid dissociation within the stomach, allowing absorption of salicylate. Over 99% of the bismuth appears in the stool. Although minimal (<1%), bismuth is absorbed; it is stored in many tissues and has slow renal excretion. Salicylate (like aspirin) is readily absorbed and excreted in the urine.


Pharmacology_Katzung

Pharmacology_Katzung. The precise mechanisms of action of bismuth are unknown. Bismuth coats ulcers and erosions, creating a protective layer against acid and pepsin. It may also stimulate prostaglandin, mucus, and bicarbonate secretion. Bismuth subsalicylate reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandin and chloride secretion. Bismuth has direct antimicrobial effects and binds enterotoxins, accounting for its benefit in preventing and treating traveler’s diarrhea. Bismuth compounds have direct antimicrobial activity against H pylori. Despite the lack of comparative trials, nonprescription bismuth compounds (eg, Pepto-Bismol, Kaopectate) are widely used by patients for the nonspecific treatment of dyspepsia and acute diarrhea. Bismuth subsalicylate also is used for the prevention of traveler’s diarrhea (30 mL or two tablets four times daily).


Pharmacology_Katzung

Pharmacology_Katzung. Bismuth compounds are used in four-drug regimens for the eradication of H pylori infection (see earlier discussion of H pylori-associated ulcers). One regimen consists of a PPI twice daily combined with bismuth subsalicylate (two tablets; 262 mg each), tetracycline (250–500 mg), and metronidazole (500 mg) four times daily for 10–14 days. Another regimen consists of a PPI twice daily combined with three capsules of a combination prescription formulation (each capsule containing bismuth subcitrate 140 mg, metronidazole 125 mg, and tetracycline 125 mg) taken four times daily for 10–14 days.


Pharmacology_Katzung

Pharmacology_Katzung. All bismuth formulations have excellent safety profiles. Bismuth causes harmless blackening of the stool, which may be confused with gastrointestinal bleeding. Liquid formulations may cause harmless darkening of the tongue. Bismuth agents should be used for short periods only and should be avoided in patients with renal insufficiency. Prolonged usage of some bismuth compounds may rarely lead to bismuth toxicity, resulting in encephalopathy (ataxia, headaches, confusion, seizures). However, such toxicity is not reported with bismuth subsalicylate or bismuth citrate. High dosages of bismuth subsalicylate may lead to salicylate toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that can selectively stimulate gut motor function (prokinetic agents) have significant potential clinical usefulness. Agents that increase lower esophageal sphincter pressures may be useful for GERD. Drugs that improve gastric emptying may be helpful for gastroparesis and postsurgical gastric emptying delay. Agents that stimulate the small intestine may be beneficial for postoperative ileus or chronic intestinal pseudo-obstruction. Finally, agents that enhance colonic transit may be useful in the treatment of constipation. Unfortunately, only a limited number of agents in this group are available for clinical use at this time. Physiology of the Enteric Nervous System


Pharmacology_Katzung

Pharmacology_Katzung. Physiology of the Enteric Nervous System The enteric nervous system (see also Chapter 6) is composed of interconnected networks of ganglion cells and nerve fibers mainly located in the submucosa (submucosal plexus) and between the circular and longitudinal muscle layers (myenteric plexus). These networks give rise to nerve fibers that connect with the mucosa and muscle. Although extrinsic sympathetic and parasympathetic nerves project onto the submucosal and myenteric plexuses, the enteric nervous system can independently regulate gastrointestinal motility and secretion. Extrinsic primary afferent neurons project via the dorsal root ganglia or vagus nerve to the central nervous system (Figure 62–4). Release of serotonin (5-HT) from intestinal mucosa enterochromaffin (EC) cells stimulates 5-HT3 receptors on the extrinsic afferent nerves, stimulating nausea, vomiting, or ACh, CGRP


Pharmacology_Katzung

Pharmacology_Katzung. ACh, CGRP Dorsal root or cranial nerve afferent 5HT3R 5HTIPR 5HT Submucosal IPAN Pressure, other stimuli EC Gut lumen –+


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 62–4 Release of serotonin (5-HT) by enterochromaffin (EC) cells from gut distention stimulates submucosal intrinsic primary afferent neurons (IPANs) via 5-HT1P receptors and extrinsic primary afferent neurons via 5-HT3 receptors (5-HT1PR, 5-HT3R). Submucosal IPANs activate the enteric neurons responsible for peristaltic and secretory reflex activity. Stimulation of 5-HT4 receptors (5-HT4R) on presynaptic terminals of IPANs enhances release of acetylcholine (ACh) and calcitonin gene-related peptide (CGRP), promoting reflex activity. CNS, central nervous system; ENS, enteric nervous system. (Data from Gershon MD: Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Dis 2003;3[Suppl 2]:S25.) abdominal pain. Serotonin also stimulates submucosal 5-HT1P receptors of the intrinsic primary afferent nerves (IPANs), which contain calcitonin gene-related peptide (CGRP) and acetylcholine and project to myenteric plexus interneurons. 5-HT4


Pharmacology_Katzung

Pharmacology_Katzung. 5-HT1P receptors of the intrinsic primary afferent nerves (IPANs), which contain calcitonin gene-related peptide (CGRP) and acetylcholine and project to myenteric plexus interneurons. 5-HT4 receptors on the presynaptic terminals of the IPANs appear to enhance release of CGRP or acetylcholine. The myenteric interneurons are important in controlling the peristaltic reflex, promoting release of excitatory mediators proximally and inhibitory mediators distally. Motilin may stimulate excitatory neurons or muscle cells directly. Dopamine acts as an inhibitory neurotransmitter in the gastrointestinal tract, decreasing the intensity of esophageal and gastric contractions.


Pharmacology_Katzung

Pharmacology_Katzung. Although there are at least 14 serotonin receptor subtypes, 5-HT drug development for gastrointestinal applications to date has focused on 5-HT3-receptor antagonists and 5-HT4-receptor agonists. These agents—which have effects on gastrointestinal motility and visceral afferent sensation—are discussed under Drugs Used in the Treatment of Gastrointestinal Diseases 1097 Drugs Used in the Treatment of Irritable Bowel Syndrome and Antiemetic Agents. Other drugs acting on 5-HT receptors are discussed in Chapters 16, 29, and 30.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs Used in the Treatment of Irritable Bowel Syndrome and Antiemetic Agents. Other drugs acting on 5-HT receptors are discussed in Chapters 16, 29, and 30. Cholinomimetic agonists such as bethanechol stimulate muscarinic M3 receptors on muscle cells and at myenteric plexus synapses (see Chapter 7). Bethanechol was used in the past for the treatment of GERD and gastroparesis. Owing to multiple cholinergic effects and the advent of less toxic agents, it is now seldom used. The acetylcholinesterase inhibitor neostigmine can enhance gastric, small intestine, and colonic emptying. Intravenous neostigmine is used for the treatment of hospitalized patients with acute large bowel distention (known as acute colonic pseudo-obstruction or Ogilvie’s syndrome). Administration of 2 mg results in prompt colonic evacuation of flatus and feces in the majority of patients. Cholinergic effects include excessive salivation, nausea, vomiting, diarrhea, and bradycardia.


Pharmacology_Katzung

Pharmacology_Katzung. Metoclopramide and domperidone are dopamine D2-receptor antagonists. Within the gastrointestinal tract, activation of dopamine receptors inhibits cholinergic smooth muscle stimulation; blockade of this effect is believed to be the primary prokinetic mechanism of action of these agents. These agents increase esophageal peristaltic amplitude, increase lower esophageal sphincter pressure, and enhance gastric emptying but have no effect on small intestine or colonic motility. Metoclopramide and domperidone also block dopamine D2 receptors in the chemoreceptor trigger zone of the medulla (area postrema), resulting in potent antinausea and antiemetic action. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Gastroesophageal reflux disease—Metoclopramide is available for clinical use in the USA; domperidone is available in many other countries. These agents are sometimes used in the treatment of symptomatic GERD but are not effective in patients with erosive esophagitis. Because of the superior efficacy and safety of antisecretory agents in the treatment of heartburn, prokinetic agents are used mainly in combination with antisecretory agents in patients with regurgitation or refractory heartburn. 2. Impaired gastric emptying—These agents are widely used in the treatment of patients with delayed gastric emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis. Metoclopramide is sometimes administered in hospitalized patients to promote advancement of nasoenteric feeding tubes from the stomach into the duodenum. 3. Nonulcer dyspepsia—These agents lead to symptomatic improvement in a small number of patients with chronic dyspepsia. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Nonulcer dyspepsia—These agents lead to symptomatic improvement in a small number of patients with chronic dyspepsia. 4. Prevention of vomiting—Because of their potent antiemetic action, metoclopramide and domperidone are used for the prevention and treatment of emesis. 5. Postpartum lactation stimulation—Domperidone is sometimes recommended to promote postpartum lactation (see also Adverse Effects).


Pharmacology_Katzung

Pharmacology_Katzung. 5. Postpartum lactation stimulation—Domperidone is sometimes recommended to promote postpartum lactation (see also Adverse Effects). The most common adverse effects of metoclopramide involve the central nervous system. Restlessness, drowsiness, insomnia, anxiety, and agitation occur in 10–20% of patients, especially the elderly. Extrapyramidal effects (dystonias, akathisia, parkinsonian features) due to central dopamine receptor blockade occur acutely in 25% of patients given high doses and in 5% of patients receiving long-term therapy. Tardive dyskinesia, sometimes irreversible, has developed in patients treated for a prolonged period with metoclopramide. For this reason, long-term use should be avoided unless absolutely necessary, especially in the elderly. Elevated prolactin levels (caused by both metoclopramide and domperidone) can cause galactorrhea, gynecomastia, impotence, and menstrual disorders.


Pharmacology_Katzung

Pharmacology_Katzung. Domperidone is extremely well tolerated. Because it does not cross the blood-brain barrier to a significant degree, neuropsychiatric and extrapyramidal effects are rare. Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle and promote the onset of a migrating motor complex. Intravenous erythromycin (3 mg/kg) is beneficial in some patients with gastroparesis; however, tolerance rapidly develops. It may be used in patients with acute upper gastrointestinal hemorrhage to promote gastric emptying of blood before endoscopy.


Pharmacology_Katzung

Pharmacology_Katzung. The overwhelming majority of people do not need laxatives; yet they are self-prescribed by a large portion of the population. For most people, intermittent constipation is best prevented with a high-fiber diet, adequate fluid intake, regular exercise, and the heeding of nature’s call. Patients not responding to dietary changes or fiber supplements should undergo medical evaluation before initiating long-term laxative treatment. Laxatives may be classified by their major mechanism of action, but many work through more than one mechanism. Bulk-forming laxatives are indigestible, hydrophilic colloids that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. Common preparations include natural plant products (psyllium, methylcellulose) and synthetic fibers (polycarbophil). Bacterial digestion of plant fibers within the colon may lead to increased bloating and flatus.


Pharmacology_Katzung

Pharmacology_Katzung. These agents soften stool material, permitting water and lipids to penetrate. They may be administered orally or rectally. Common agents include docusate (oral or enema) and glycerin suppository. In hospitalized patients, docusate is commonly prescribed to prevent constipation and minimize straining. Mineral oil is a clear, viscous oil that lubricates fecal material, retarding water absorption from the stool. It is used to prevent and treat fecal impaction in young children and debilitated adults. It is not palatable but may be mixed with juices. Aspiration can result in a severe lipid pneumonitis. Long-term use can impair absorption of fat-soluble vitamins (A, D, E, K). The colon can neither concentrate nor dilute fecal fluid: fecal water is isotonic throughout the colon. Osmotic laxatives are soluble but nonabsorbable compounds that result in increased stool liquidity due to an obligate increase in fecal fluid.


Pharmacology_Katzung

Pharmacology_Katzung. These agents may be used for the treatment of acute constipation or the prevention of chronic constipation. Magnesium hydroxide (milk of magnesia) is a commonly used osmotic laxative. It should not be used for prolonged periods in patients with renal insufficiency due to the risk of hypermagnesemia. Sorbitol and lactulose are nonabsorbable sugars that can be used to prevent or treat chronic constipation. These sugars are metabolized by colonic bacteria, producing severe flatus and cramps.


Pharmacology_Katzung

Pharmacology_Katzung. High doses of osmotically active agents produce prompt bowel evacuation (purgation) within 1–3 hours. The rapid movement of water into the distal small bowel and colon leads to a high volume of liquid stool followed by bowel evacuation. Several purgatives are available, which may be used for the treatment of acute constipation or to cleanse the bowel prior to medical procedures (eg, colonoscopy). These include magnesium citrate, sulfate solution, and a proprietary combination of magnesium oxide, sodium picosulfate, and citrate (Prepopik). When taking these purgatives, it is very important that patients maintain adequate hydration by taking increased oral liquids to compensate for fecal fluid loss. Sodium phosphate also is available—by prescription—as a tablet formulation but is infrequently used due to the risk of hyperphosphatemia, hypocalcemia, hypernatremia, and hypokalemia. Although these electrolyte abnormalities are clinically insignificant in most patients, they may lead to


Pharmacology_Katzung

Pharmacology_Katzung. used due to the risk of hyperphosphatemia, hypocalcemia, hypernatremia, and hypokalemia. Although these electrolyte abnormalities are clinically insignificant in most patients, they may lead to cardiac arrhythmias or acute renal failure due to tubular deposition of calcium phosphate (nephrocalcinosis). Sodium phosphate preparations should not be used in patients who are frail or elderly, have renal insufficiency, have significant cardiac disease, or are unable to maintain adequate hydration during bowel preparation.


Pharmacology_Katzung

Pharmacology_Katzung. Lavage solutions containing polyethylene glycol (PEG) are commonly used for complete colonic cleansing before gastrointestinal endoscopic procedures. These balanced, isotonic solutions contain an inert, nonabsorbable, osmotically active sugar (PEG) with sodium sulfate, sodium chloride, sodium bicarbonate, and potassium chloride. The solution is designed so that no significant intravascular fluid or electrolyte shifts occur. Therefore, they are safe for all patients. For optimal bowel cleansing, 1–2 L of solution should be ingested rapidly (over 1–2 hours) on the evening before the procedure and again 4–6 hours before the procedure. For treatment or prevention of chronic constipation, smaller doses of PEG powder may be mixed with water or juices (17 g/8 oz) and ingested daily. In contrast to sorbitol or lactulose, PEG does not produce significant cramps or flatus.


Pharmacology_Katzung

Pharmacology_Katzung. Stimulant laxatives (cathartics) induce bowel movements through a number of poorly understood mechanisms. These include direct stimulation of the enteric nervous system and colonic electrolyte and fluid secretion. There has been concern that long-term use of cathartics could lead to dependence and destruction of the myenteric plexus, resulting in colonic atony and dilation. More recent research suggests that long-term use of these agents probably is safe in most patients. Cathartics may be required on a long-term basis, especially in patients who are neurologically impaired and in bed-bound patients in long-term care facilities.


Pharmacology_Katzung

Pharmacology_Katzung. Aloe, senna, and cascara occur naturally in plants. These laxatives are poorly absorbed and after hydrolysis in the colon, produce a bowel movement in 6–12 hours when given orally and within 2 hours when given rectally. Chronic use leads to a characteristic brown pigmentation of the colon known as “melanosis coli.” There has been some concern that these agents may be carcinogenic, but epidemiologic studies do not suggest a relation to colorectal cancer. Bisacodyl is available in tablet and suppository formulations for the treatment of acute and chronic constipation. It also is used in conjunction with PEG solutions for colonic cleansing prior to colonoscopy. It induces a bowel movement within 6–10 hours when given orally and 30–60 minutes when taken rectally. It has minimal systemic absorption and appears to be safe for acute and long-term use.


Pharmacology_Katzung

Pharmacology_Katzung. Lubiprostone is a prostanoic acid derivative labeled for use in chronic constipation and irritable bowel syndrome (IBS) with predominant constipation. It acts by stimulating the type 2 chloride channel (ClC-2) in the small intestine. This increases chloride-rich fluid secretion into the intestine, which stimulates intestinal motility and shortens intestinal transit time. Over 50% of patients experience a bowel movement within 24 hours of taking one dose. A dose of 24 mcg orally twice daily is the recommended dose for treatment of chronic constipation. There appears to be no loss of efficacy with long-term therapy. After discontinuation of the drug, constipation may return to its pretreatment severity. Lubiprostone has minimal systemic absorption but is designated category C for pregnancy because of increased fetal loss in guinea pigs. Lubiprostone may cause nausea in up to 30% of patients due to delayed gastric emptying.


Pharmacology_Katzung

Pharmacology_Katzung. Linaclotide and plecanatide are minimally absorbed, short amino acid peptides that stimulate intestinal chloride secretion through a different mechanism by binding to and activating guanylate cyclase-C on the luminal surface. This leads to increased intracellular and extracellular cyclic guanosine monophosphate (cGMP) with activation of the cystic fibrosis transmembrane conductance regulator (CFTR), followed by chloride-rich secretion and acceleration of intestinal transit. Both agents are approved for the treatment of chronic constipation (linaclotide 145 mcg orally once daily; plecanatide 3 mg orally once daily); linaclotide is also approved for the treatment of irritable bowel syndrome with constipation (290 mcg orally once daily). These agents result in an average increase of 1–2 bowel movements per week that usually occurs within the first week of treatment. Upon discontinuation of the drug, bowel movement frequency returns to normal within 1 week. The most common side effect is


Pharmacology_Katzung

Pharmacology_Katzung. movements per week that usually occurs within the first week of treatment. Upon discontinuation of the drug, bowel movement frequency returns to normal within 1 week. The most common side effect is diarrhea, which occurs in up to 20% of patients, with severe diarrhea in 2%. These drugs have negligible absorption at standard doses. Both drugs are contraindicated in pediatric patients because of reports of increased mortality in juvenile mice from dehydration. (Crofelemer is a small molecule with the opposite effect: it is an inhibitor of the CFTR channel and has recently been approved for the treatment of HIV-drug-induced diarrhea.)


Pharmacology_Katzung

Pharmacology_Katzung. Acute and chronic therapy with opioids may cause constipation by decreasing intestinal motility, which results in prolonged transit time and increased absorption of fecal water (see Chapter 31). Use of opioids after surgery for treatment of pain as well as endogenous opioids also may prolong the duration of postoperative ileus. These effects are mainly mediated through intestinal mu (μ)-opioid receptors. Two selective antagonists of the μ-opioid receptor are commercially available: methylnaltrexone bromide and alvimopan. Because these agents do not readily cross the blood-brain barrier, they inhibit peripheral μ-opioid receptors without impacting analgesic effects within the central nervous system. Methylnaltrexone is approved for the treatment of opioid-induced constipation in patients receiving palliative care for advanced illness who have had inadequate response to other agents. It is administered as a subcutaneous injection (0.15 mg/ kg) every 2 days. Alvimopan is approved for


Pharmacology_Katzung

Pharmacology_Katzung. receiving palliative care for advanced illness who have had inadequate response to other agents. It is administered as a subcutaneous injection (0.15 mg/ kg) every 2 days. Alvimopan is approved for short-term use to shorten the period of postoperative ileus in hospitalized patients who have undergone small or large bowel resection. Alvimopan (12 mg capsule) is administered orally within 5 hours before surgery and twice daily after surgery until bowel function has recovered, but for no more than 7 days. Because of possible cardiovascular toxicity, alvimopan currently is restricted to short-term use in hospitalized patients only.


Pharmacology_Katzung

Pharmacology_Katzung. Stimulation of 5-HT4 receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves enhances the release of their neurotransmitters, including calcitonin gene-related peptide, which stimulates second-order enteric neurons to promote the peristaltic reflex (Figure 62–4). These enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide).


Pharmacology_Katzung

Pharmacology_Katzung. Tegaserod is a serotonin 5-HT4 partial agonist that has high affinity for 5-HT4 receptors but no appreciable binding to 5-HT3 or dopamine receptors. Tegaserod was approved for the treatment of patients with chronic constipation and IBS with predominant constipation. It has since been withdrawn. Prucalopride is a high-affinity 5-HT4 agonist that is available in Europe (but not in the USA) for the treatment of chronic constipation in women. In contrast to cisapride and tegaserod, it does not appear to have significant affinities for either hERG K+ channels or 5-HT1B receptors. In three 12-week clinical trials of patients with severe chronic constipation, it resulted in a significant increase in bowel movements compared with placebo. The long-term efficacy and safety of this agent require further study.


Pharmacology_Katzung

Pharmacology_Katzung. Antidiarrheal agents may be used safely in patients with mild to moderate acute diarrhea. However, these agents should not be used in patients with bloody diarrhea, high fever, or systemic toxicity because of the risk of worsening the underlying condition. They should be discontinued in patients whose diarrhea is worsening despite therapy. Antidiarrheals are also used to control chronic diarrhea caused by such conditions as IBS or inflammatory bowel disease (IBD). As previously noted, opioids have significant constipating effects (see Chapter 31). They increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption. They also decrease mass colonic movements and the gastrocolic reflex. Although all opioids have antidiarrheal effects, central nervous system effects and potential for addiction limit the usefulness of most.


Pharmacology_Katzung

Pharmacology_Katzung. Loperamide is a nonprescription opioid agonist that does not cross the blood-brain barrier and has no analgesic properties or potential for addiction. Tolerance to long-term use has not been reported. It is typically administered in doses of 2 mg taken one to four times daily. Diphenoxylate is a prescription opioid agonist that has no analgesic properties in standard doses; however, higher doses have central nervous system effects, and prolonged use can lead to opioid dependence. Commercial preparations commonly contain small amounts of atropine to discourage overdosage (2.5 mg diphenoxylate with 0.025 mg atropine). The anticholinergic properties of atropine may contribute to the antidiarrheal action.


Pharmacology_Katzung

Pharmacology_Katzung. Eluxadoline is a prescription opioid agonist with high affinity for the mu receptor (as well as low affinity for the delta receptor). When taken orally, eluxadoline binds to gut opioid receptors, resulting in slower colonic transit and increased fecal fluid absorption. Eluxadoline is approved for the treatment of patients with diarrhea-predominant IBS at a dose of 75–100 mg twice daily. In two randomized placebo-controlled trials, eluxadoline 100 mg twice daily led to significant improvement in abdominal pain and diarrhea in 30% of patients compared with 16% with placebo. Constipation may occur in 8% of patients. Approximately 1% of patients may experience sphincter of Oddi spasm (usually within the first week of therapy) resulting in abdominal pain, pancreatitis, and/or elevated pancreatic or liver enzymes. Eluxadoline should not be used in patients with a history of pancreatitis, alcoholism, or known sphincter of Oddi disease. Caution is advised in patients with prior


Pharmacology_Katzung

Pharmacology_Katzung. pancreatic or liver enzymes. Eluxadoline should not be used in patients with a history of pancreatitis, alcoholism, or known sphincter of Oddi disease. Caution is advised in patients with prior cholecystectomy, in whom there is up to a 5% risk of complications due to sphincter of Oddi spasm. Eluxadoline 75 mg twice daily is recommended for patients with prior cholecystectomy, mild to moderate liver disease, or side effects at the higher dose.


Pharmacology_Katzung

Pharmacology_Katzung. See the section under Mucosal Protective Agents in earlier text.


Pharmacology_Katzung

Pharmacology_Katzung. Conjugated bile salts are normally absorbed in the terminal ileum. Disease of the terminal ileum (eg, Crohn’s disease) or surgical resection leads to malabsorption of bile salts, which may cause colonic secretory diarrhea. The bile salt-binding resins cholestyramine, colestipol, or colesevelam, may decrease diarrhea caused by excess fecal bile acids (see Chapter 35). These products come in a variety of powder and pill formulations that may be taken one to three times daily before meals. Adverse effects include bloating, flatulence, constipation, and fecal impaction. In patients with diminished circulating bile acid pools, further removal of bile acids may lead to an exacerbation of fat malabsorption. Cholestyramine and colestipol bind a number of drugs and reduce their absorption; hence, they should not be given within 2 hours of other drugs. Colesevelam does not appear to have significant effects on absorption of other drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Somatostatin is a 14-amino-acid peptide that is released in the gastrointestinal tract and pancreas from paracrine cells, D cells, and enteric nerves as well as from the hypothalamus (see Chapter 37). Somatostatin is a key regulatory peptide that has many physiologic effects: 1. It inhibits the secretion of numerous hormones and transmitters, including gastrin, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, vasoactive intestinal peptide, and 5-HT. 2. It reduces intestinal fluid secretion and pancreatic secretion. 3. It slows gastrointestinal motility and inhibits gallbladder contraction. 4. It reduces portal and splanchnic blood flow. 5. It inhibits secretion of some anterior pituitary hormones.


Pharmacology_Katzung

Pharmacology_Katzung. 3. It slows gastrointestinal motility and inhibits gallbladder contraction. 4. It reduces portal and splanchnic blood flow. 5. It inhibits secretion of some anterior pituitary hormones. The clinical usefulness of somatostatin is limited by its short half-life in the circulation (3 minutes) when it is administered by intravenous injection. Octreotide is a synthetic octapeptide with actions similar to somatostatin. When administered intravenously, it has a serum half-life of 1.5 hours. It also may be administered by subcutaneous injection, resulting in a 6to 12-hour duration of action. A longer-acting formulation is available for once-monthly depot intramuscular injection. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Inhibition of endocrine tumor effects—Two gastrointestinal neuroendocrine tumors (carcinoid, VIPoma) cause secretory diarrhea and systemic symptoms such as flushing and wheezing. For patients with advanced symptomatic tumors that cannot be completely removed by surgery, octreotide decreases secretory diarrhea and systemic symptoms through inhibition of hormonal secretion and may slow tumor progression. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Other causes of diarrhea—Octreotide inhibits intestinal secretion and has dose-related effects on bowel motility. In low doses (50 mcg subcutaneously), it stimulates motility, whereas at higher doses (eg, 100–250 mcg subcutaneously), it inhibits motility. Octreotide is effective in higher doses for the treatment of diarrhea due to vagotomy or dumping syndrome as well as for diarrhea caused by short bowel syndrome or AIDS. Octreotide has been used in low doses (50 mcg subcutaneously) to stimulate small bowel motility in patients with small bowel bacterial overgrowth or intestinal pseudo-obstruction secondary to scleroderma. 3. Other uses—Because it inhibits pancreatic secretion, octreotide may be of value in patients with pancreatic fistula. The role of octreotide in the treatment of pituitary tumors (eg, acromegaly) is discussed in Chapter 37. Octreotide is sometimes used in gastrointestinal bleeding (see below).


Pharmacology_Katzung

Pharmacology_Katzung. Impaired pancreatic secretion may cause steatorrhea, which can lead to fat-soluble vitamin deficiency. Alterations in gastrointestinal motility cause nausea, abdominal pain, flatulence, and diarrhea. Because of inhibition of gallbladder contractility and alterations in fat absorption, long-term use of octreotide can cause formation of sludge or gallstones in over 50% of patients, which rarely results in the development of acute cholecystitis. Because octreotide alters the balance among insulin, glucagon, and growth hormone, hyperglycemia or, less frequently, hypoglycemia (usually mild) can occur. Prolonged treatment with octreotide may result in hypothyroidism. Octreotide also can cause bradycardia.


Pharmacology_Katzung

Pharmacology_Katzung. IBS is an idiopathic chronic, relapsing disorder characterized by abdominal discomfort (pain, bloating, distention, or cramps) in association with alterations in bowel habits (diarrhea, constipation, or both). With episodes of abdominal pain or discomfort, patients note a change in the frequency or consistency of their bowel movements. Pharmacologic therapies for IBS are directed at relieving abdominal pain and discomfort and improving bowel function. For patients with predominant diarrhea, antidiarrheal agents, especially loperamide, are helpful in reducing stool frequency and fecal urgency. For patients with predominant constipation, fiber supplements may lead to softening of stools and reduced straining; however, increased gas production may exacerbate bloating and abdominal discomfort. Consequently, osmotic laxatives, especially milk of magnesia, are commonly used to soften stools and promote increased stool frequency.


Pharmacology_Katzung

Pharmacology_Katzung. For chronic abdominal pain, low doses of tricyclic antidepressants (eg, amitriptyline or desipramine, 10–50 mg/d) appear to be helpful (see Chapter 30). At these doses, these agents have no effect on mood but may alter central processing of visceral afferent information. The anticholinergic properties of these agents also may have effects on gastrointestinal motility and secretion, reducing stool frequency and liquidity. Finally, tricyclic antidepressants may alter receptors for enteric neurotransmitters such as serotonin, affecting visceral afferent sensation. Several other agents are available that are specifically intended for the treatment of IBS.


Pharmacology_Katzung

Pharmacology_Katzung. Several other agents are available that are specifically intended for the treatment of IBS. Some agents are promoted as providing relief of abdominal pain or discomfort through antispasmodic actions. However, small or large bowel spasm has not been found to be an important cause of symptoms in patients with IBS. Antispasmodics work primarily through anticholinergic activities. Commonly used medications in this class include dicyclomine and hyoscyamine (see Chapter 8). These drugs inhibit muscarinic cholinergic receptors in the enteric plexus and on smooth muscle. The efficacy of antispasmodics for relief of abdominal symptoms has never been convincingly demonstrated. At low doses, they have minimal autonomic effects. However, at higher doses they exhibit significant additional anticholinergic effects, including dry mouth, visual disturbances, urinary retention, and constipation. For these reasons, antispasmodics are infrequently used.


Pharmacology_Katzung

Pharmacology_Katzung. 5-HT3 receptors in the gastrointestinal tract activate visceral afferent pain sensation via extrinsic sensory neurons from the gut to the spinal cord and central nervous system. Inhibition of afferent gastrointestinal 5-HT3 receptors may reduce unpleasant visceral afferent sensation, including nausea, bloating, and pain. Blockade of central 5-HT3 receptors also reduces the central response to visceral afferent stimulation. In addition, 5-HT3-receptor blockade on the terminals of enteric cholinergic neurons inhibits colonic motility, especially in the left colon, increasing total colonic transit time.


Pharmacology_Katzung

Pharmacology_Katzung. Alosetron is a 5-HT3 antagonist that has been approved for the treatment of patients with severe IBS with diarrhea (Figure 62–5). Four other 5-HT3 antagonists (ondansetron, granisetron, dolasetron, and palonosetron) have been approved for the prevention and treatment of nausea and vomiting (see Antiemetics); however, their efficacy in the treatment of IBS has not been determined. The differences between these 5-HT3 antagonists that determine their pharmacodynamic effects have not been well studied.


Pharmacology_Katzung

Pharmacology_Katzung. Alosetron is a highly potent and selective antagonist of the 5-HT3 receptor. It is rapidly absorbed from the gastrointestinal tract with a bioavailability of 50–60% and has a plasma half-life of 1.5 hours but a much longer duration of effect. It undergoes extensive hepatic cytochrome P450 metabolism with renal excretion of most metabolites. Alosetron binds with higher affinity and dissociates more slowly from 5-HT3 receptors than other 5-HT3 antagonists, which may account for its long duration of action. Alosetron is approved for the treatment of women with severe IBS in whom diarrhea is the predominant symptom FIGURE 62–5 Chemical structure of serotonin; the 5-HT3 antagonists ondansetron, granisetron, dolasetron, and alosetron; and the 5-HT4 partial agonist tegaserod.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 62–5 Chemical structure of serotonin; the 5-HT3 antagonists ondansetron, granisetron, dolasetron, and alosetron; and the 5-HT4 partial agonist tegaserod. (“diarrhea-predominant IBS”). Its efficacy in men has not been established. In a dosage of 1 mg once or twice daily, it reduces IBS-related lower abdominal pain, cramps, urgency, and diarrhea. Approximately 50–60% of patients report adequate relief of pain and discomfort with alosetron compared with 30–40% of patients treated with placebo. It also leads to a reduction in the mean number of bowel movements per day and improvement in stool consistency. Alosetron has not been evaluated for the treatment of other causes of diarrhea.


Pharmacology_Katzung

Pharmacology_Katzung. In contrast to the excellent safety profile of other 5-HT3-receptor antagonists, alosetron is associated with rare but serious gastrointestinal toxicity. Constipation occurs in up to 30% of patients with diarrhea-predominant IBS, requiring discontinuation of the drug in 10%. Serious complications of constipation requiring hospitalization or surgery have occurred in 1 of every 1000 patients. Episodes of ischemic colitis—some fatal—have been reported in up to 3 per 1000 patients. Given the seriousness of these adverse events, alosetron is restricted to women with severe diarrhea-predominant IBS who have not responded to conventional therapies and who have been educated about the relative risks and benefits. Despite being metabolized by a number of CYP enzymes, alosetron does not appear to have clinically significant interactions with other drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Despite being metabolized by a number of CYP enzymes, alosetron does not appear to have clinically significant interactions with other drugs. As discussed previously, lubiprostone is a prostanoic acid derivative that stimulates the type 2 chloride channel (ClC-2) in the small intestine. Lubiprostone is approved for the treatment of women with IBS with predominant constipation. Its efficacy for men with IBS is unproven. The approved dose for IBS is 8 mcg twice daily (compared with 24 mcg twice daily for chronic constipation). In clinical trials, lubiprostone resulted in modest clinical benefit—only 8% more patients than with placebo. Lubiprostone is listed as category C for pregnancy and should be avoided in women of child-bearing age.


Pharmacology_Katzung

Pharmacology_Katzung. Also discussed previously, linaclotide is a guanylyl cyclase-C agonist that leads to activation of the CFTR in the small intestine with stimulation of chloride-rich intestinal secretion. It is approved for treatment of adults with IBS with constipation at an approved dose of 290 mcg once daily (compared with 145 mcg once daily for chronic constipation). In clinical trials, up to 25% more patients treated with linaclotide than with placebo demonstrated significant clinical improvement. Linaclotide is listed as category C for pregnancy and is contraindicated for pediatric patients. Due to their high cost and lack of information about long-term safety and efficacy, the role of these agents in the treatment of IBS with constipation is uncertain. Neither agent has been compared with other less expensive laxatives (eg, milk of magnesia).


Pharmacology_Katzung

Pharmacology_Katzung. Nausea and vomiting may be manifestations of a wide variety of conditions, including adverse effects from medications; systemic disorders or infections; pregnancy; vestibular dysfunction; central nervous system infection or increased pressure; peritonitis; hepatobiliary disorders; radiation or chemotherapy; and gastrointestinal obstruction, dysmotility, or infections. The brainstem “vomiting center” is a loosely organized neuronal region within the lateral medullary reticular formation and coordinates the complex act of vomiting through interactions with cranial nerves VIII and X and neural networks in the nucleus tractus solitarius that control respiratory, salivatory, and vasomotor centers. High concentrations of muscarinic M1, histamine H1, neurokinin 1 (NK1), and serotonin 5-HT3 receptors have been identified in the vomiting center (Figure 62–6). There are four important sources of afferent input to the vomiting center: 1.


Pharmacology_Katzung

Pharmacology_Katzung. There are four important sources of afferent input to the vomiting center: 1. The “chemoreceptor trigger zone” or area postrema is located at the caudal end of the fourth ventricle. This is outside the blood-brain barrier and is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. The chemoreceptor trigger zone is rich in dopamine D2 receptors and opioid receptors, and possibly serotonin 5-HT3 receptors and NK1 receptors. 2. The vestibular system is important in motion sickness via cranial nerve VIII. It is rich in muscarinic M1 and histamine H1 receptors. 3. Vagal and spinal afferent nerves from the gastrointestinal tract are rich in 5-HT3 receptors. Irritation of the gastrointestinal mucosa by chemotherapy, radiation therapy, distention, or acute infectious gastroenteritis leads to release of mucosal serotonin and activation of these receptors, which stimulate vagal afferent input to the vomiting center and chemoreceptor trigger zone. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. The central nervous system plays a role in vomiting due to psychiatric disorders, stress, and anticipatory vomiting prior to cancer chemotherapy. Identification of the different neurotransmitters involved with emesis has allowed development of a diverse group of antiemetic agents that have affinity for various receptors. Combinations of antiemetic agents with different mechanisms of action are often used, especially in patients with vomiting due to chemotherapeutic agents. Selective 5-HT3-receptor antagonists have potent antiemetic properties that are mediated in part through central 5-HT3receptor blockade in the vomiting center and chemoreceptor


Pharmacology_Katzung

Pharmacology_Katzung. Selective 5-HT3-receptor antagonists have potent antiemetic properties that are mediated in part through central 5-HT3receptor blockade in the vomiting center and chemoreceptor Central nervous system Gastrointestinal tract and heart Vestibular system Fourth ventricle Medulla oblongata Parasympathetic and motor efferent activity Vomiting center Chemoreceptor trigger zone H1 receptor M1 receptor NK1 receptor? (5-HT3 receptor) Vomiting center (nucleus of tractus solitarius) Chemoreceptors D2 receptor NK1 receptor? (5-HT3 receptor) Chemoreceptor trigger zone (area postrema) H1 receptor? M1 receptor Mechanoreceptors Chemoreceptors 5-HT3 receptor Cortex Thalamus Hypothalamus Meninges Cranialnerve IXorX


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 62–6 Neurologic pathways involved in pathogenesis of nausea and vomiting (see text). (Adapted, with permission, from Krakauer EL et al: Case records of the Massachusetts General Hospital. N Engl J Med 2005;352:817. Copyright copy; 2005 Massachusetts Medical Society. Reprinted, with permission, from Massachusetts Medical Society.) trigger zone but mainly through blockade of peripheral 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves. The antiemetic action of these agents is restricted to emesis attributable to vagal stimulation (eg, postoperative) and chemotherapy; other emetic stimuli such as motion sickness are poorly controlled.


Pharmacology_Katzung

Pharmacology_Katzung. Four agents are available in the USA: ondansetron, granisetron, dolasetron, and palonosetron. (Tropisetron is available outside the USA.) The first three agents (ondansetron, granisetron, and dolasetron, Figure 62–5) have a serum half-life of 4–9 hours and may be administered once daily by oral or intravenous routes. All three drugs have comparable efficacy and tolerability when administered at equipotent doses. Palonosetron is a newer intravenous agent that has greater affinity for the 5-HT3 receptor and a long serum half-life of 40 hours. All four drugs undergo extensive hepatic metabolism and are eliminated by renal and hepatic excretion. However, dose reduction is not required in geriatric patients or patients with renal insufficiency. For patients with hepatic insufficiency, dose reduction may be required with ondansetron.


Pharmacology_Katzung

Pharmacology_Katzung. 5-HT3-receptor antagonists do not inhibit dopamine or muscarinic receptors. They do not have effects on esophageal or gastric motility but may slow colonic transit. 1.


Pharmacology_Katzung

Pharmacology_Katzung. Chemotherapy-induced nausea and vomiting—5-HT3receptor antagonists are the primary agents for the prevention of acute chemotherapy-induced nausea and emesis. When used alone, these drugs have little or no efficacy for the prevention of delayed nausea and vomiting (ie, occurring >24 hours after chemotherapy). The drugs are most effective when given as a single dose by intravenous injection 30 minutes prior to administration of chemotherapy in the following doses: ondansetron, 8 mg; granisetron, 1 mg; dolasetron, 100 mg; or palonosetron, 0.25 mg. A single oral dose given 1 hour before chemotherapy may be equally effective in the following regimens: ondansetron 8 mg twice daily or 24 mg once; granisetron, 2 mg; dolasetron, 100 mg. Although 5-HT3-receptor antagonists are effective as single agents for the prevention of chemotherapy-induced nausea and vomiting, their efficacy is enhanced by combination therapy with a corticosteroid (dexamethasone), NK1-receptor antagonist, and a dopamine


Pharmacology_Katzung

Pharmacology_Katzung. agents for the prevention of chemotherapy-induced nausea and vomiting, their efficacy is enhanced by combination therapy with a corticosteroid (dexamethasone), NK1-receptor antagonist, and a dopamine D2 antagonist (antipsychotics; see below).


Pharmacology_Katzung

Pharmacology_Katzung. 2. Postoperative and postradiation nausea and vomiting—5-HT3-receptor antagonists are used to prevent or treat postoperative nausea and vomiting. Because of adverse effects and increased restrictions on the use of other antiemetic agents, 5-HT3-receptor antagonists are increasingly used for this indication. They are also effective in the prevention and treatment of nausea and vomiting in patients undergoing radiation therapy to the whole body or abdomen.


Pharmacology_Katzung

Pharmacology_Katzung. The 5-HT3-receptor antagonists are well-tolerated agents with excellent safety profiles. The most commonly reported adverse effects are headache, dizziness, and constipation. All four agents cause a small but statistically significant prolongation of the QT interval, but this is most pronounced with dolasetron. Although cardiac arrhythmias have not been linked to dolasetron, it should not be administered to patients with prolonged QT or in conjunction with other medications that may prolong the QT interval (see Chapter 14). Serotonin syndrome has been reported in patients taking 5-HT3-receptor antagonists in combination with other serotonergic drugs (selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]; see Chapter 30).


Pharmacology_Katzung

Pharmacology_Katzung. No significant drug interactions have been reported with 5-HT3receptor antagonists. All four agents undergo some metabolism by the hepatic cytochrome P450 system, but they do not appear to affect the metabolism of other drugs. However, other drugs may reduce hepatic clearance of the 5-HT3-receptor antagonists, altering their half-life. Corticosteroids (dexamethasone, methylprednisolone) have anti-emetic properties, but the basis for these effects is unknown. The pharmacology of this class of drugs is discussed in Chapter 39. These agents appear to enhance the efficacy of 5-HT3-receptor antagonists for prevention of acute and delayed nausea and vomiting in patients receiving moderately to highly emetogenic chemotherapy regimens. Although a number of corticosteroids have been used, dexamethasone, 8–20 mg intravenously before chemotherapy, followed by 8 mg/d orally for 2–4 days, is commonly administered.


Pharmacology_Katzung

Pharmacology_Katzung. Neurokinin 1 (NK1)-receptor antagonists have antiemetic properties that are mediated through central blockade in the area postrema. Aprepitant, netupitant, and rolapitant (all oral formulations) are highly selective NK1-receptor antagonists that cross the blood-brain barrier and occupy brain NK1 receptors. They have no affinity for serotonin, dopamine, or corticosteroid receptors. Netupitant (300 mg) is available only as a combination product with palonosetron (0.5 mg). Fosaprepitant is an intravenous formulation that is converted within 30 minutes after infusion to aprepitant. The oral bioavailability of aprepitant is 65%, and the serum half-life is 12 hours. Netupitant and rolapitant have longer half-lives (90 and 180 hours, respectively), allowing single-dose administration. All three agents are metabolized by the liver, primarily by the CYP3A4 pathway.


Pharmacology_Katzung

Pharmacology_Katzung. NK1-receptor antagonists are used in combination with 5-HT3receptor antagonists and corticosteroids for the prevention of acute and delayed nausea and vomiting from highly emetogenic chemotherapeutic regimens. Combined therapy with an NK1-receptor antagonist, a 5-HT3-receptor antagonist, and dexamethasone prevents acute emesis in 80–90% of patients compared with less than 70% of patients treated without an NK1 antagonist. Prevention of delayed emesis occurs in more than 70% of patients receiving combined therapy versus 30–50% treated without an NK1 antagonist. Oral NK1-receptor antagonists may be administered as follows: aprepitant 125 mg given 1 hour before chemotherapy, followed by oral aprepitant 80 mg/d for 2 days after chemotherapy; rolapitant 180 mg; or netupitant 300 mg/palonosetron 0.5 mg given as a single dose 1–2 hours before chemotherapy. For patients unable to tolerate oral therapy, intravenous fosaprepitant 115 mg may be given as a single intravenous dose 1 hour before


Pharmacology_Katzung

Pharmacology_Katzung. 0.5 mg given as a single dose 1–2 hours before chemotherapy. For patients unable to tolerate oral therapy, intravenous fosaprepitant 115 mg may be given as a single intravenous dose 1 hour before chemotherapy. The addition of the antipsychotic agent olanzapine 10 mg on days 1–4 further decreases the incidence of acute and delayed nausea and vomiting with highly emetogenic chemotherapeutic regimens by 15–30%.


Pharmacology_Katzung

Pharmacology_Katzung. The NK1-receptor antagonists are well tolerated with a low incidence of fatigue and dizziness. The drugs are metabolized by CYP3A4 and may inhibit the metabolism of other drugs metabolized by the CYP3A4 pathway. Several chemotherapeutic agents are metabolized by CYP3A4, including docetaxel, paclitaxel, etoposide, irinotecan, imatinib, vinblastine, and vincristine. Drugs that inhibit CYP3A4 metabolism may significantly increase aprepitant plasma levels (eg, ketoconazole, ciprofloxacin, clarithromycin, nefazodone, ritonavir, nelfinavir, verapamil, and quinidine). Aprepitant decreases the international normalized ratio (INR) in patients taking warfarin. ANTIPSYCHOTIC AGENTS (PHENOTHIAZINES, BUTYROPHENONES, & THIENOBENZODIAZEPINES)


Pharmacology_Katzung

Pharmacology_Katzung. ANTIPSYCHOTIC AGENTS (PHENOTHIAZINES, BUTYROPHENONES, & THIENOBENZODIAZEPINES) Several classes of antipsychotic agents can be used for their anti-emetic and sedative properties (see Chapter 29). The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors. Sedative properties are due to their antihistamine activity. The agents most commonly used as antiemetics are prochlorperazine, promethazine, and thiethylperazine. The antiemetic properties of olanzapine (a thienobenzodiazepine) may be attributable to inhibition of dopamine D2 and serotonin 5-HT1c and 5-HT3 receptors.


Pharmacology_Katzung

Pharmacology_Katzung. Antipsychotic butyrophenones also possess antiemetic properties due to their central dopaminergic blockade (see Chapter 29). The main agent used is droperidol, which can be given by intramuscular or intravenous injection. In antiemetic doses, droperidol is extremely sedating. Previously, it was used extensively for postoperative nausea and vomiting, in conjunction with opiates and benzodiazepines for sedation for surgical and endoscopic procedures, for neuroleptanalgesia, and for induction and maintenance of general anesthesia. Extrapyramidal effects and hypotension may occur. Droperidol may prolong the QT interval, rarely resulting in fatal episodes of ventricular tachycardia including torsades de pointes. Therefore, droperidol should not be used in patients with QT prolongation and should be used only in patients who have not responded adequately to alternative agents.


Pharmacology_Katzung

Pharmacology_Katzung. Substituted benzamides include metoclopramide (discussed previously) and trimethobenzamide. Their primary mechanism of antiemetic action is believed to be dopamine-receptor blockade. Trimethobenzamide also has weak antihistaminic activity. For prevention and treatment of nausea and vomiting, metoclopramide may be given in the relatively high dosage of 10–20 mg orally or intravenously every 6 hours. The usual dose of trimethobenzamide is 300 mg orally, or 200 mg by intramuscular injection. The principal adverse effects of these central dopamine antagonists are extrapyramidal: restlessness, dystonias, and parkinsonian symptoms.


Pharmacology_Katzung

Pharmacology_Katzung. The pharmacology of anticholinergic agents is discussed in Chapter 8 and that of H1 antihistaminic agents in Chapter 16. As single agents, these drugs have weak antiemetic activity, although they are particularly useful for the prevention or treatment of motion sickness. Their use may be limited by dizziness, sedation, confusion, dry mouth, cycloplegia, and urinary retention. Diphenhydramine and one of its salts, dimenhydrinate, are first-generation histamine H1 antagonists that also have significant anticholinergic properties. Because of its sedating properties, diphenhydramine is commonly used in conjunction with other antiemetics for treatment of emesis due to chemotherapy. Meclizine is an H1 antihistaminic agent with minimal anticholinergic properties that also causes less sedation. It is used for the prevention of motion sickness and the treatment of vertigo due to labyrinth dysfunction.


Pharmacology_Katzung

Pharmacology_Katzung. Hyoscine (scopolamine), a prototypic muscarinic receptor antagonist, is one of the best agents for the prevention of motion sickness. However, it has a very high incidence of anticholinergic effects when given orally or parenterally. It is better tolerated as a transdermal patch. Superiority to dimenhydrinate has not been proved. Benzodiazepines such as lorazepam or diazepam are used before the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety. The pharmacology of these agents is presented in Chapter 22.


Pharmacology_Katzung

Pharmacology_Katzung. Dronabinol is Δ9-tetrahydrocannabinol (THC), the major psychoactive chemical in marijuana (see Chapter 32). After oral ingestion, the drug is almost completely absorbed but undergoes significant first-pass hepatic metabolism. Its metabolites are excreted slowly over days to weeks in the feces and urine. Like crude marijuana, dronabinol is a psychoactive agent that is used medically as an appetite stimulant and as an antiemetic, but the mechanisms for these effects are not understood. Because of the availability of more effective agents, dronabinol now is uncommonly used for the prevention of chemotherapy-induced nausea and vomiting. Combination therapy with phenothiazines provides synergistic antiemetic action and appears to attenuate the adverse effects of both agents. Dronabinol is usually administered in a dosage of 5 mg/m2 just prior to chemotherapy and every 2–4 hours as needed. Adverse effects include euphoria, dysphoria, sedation, hallucinations, dry mouth, and increased


Pharmacology_Katzung

Pharmacology_Katzung. usually administered in a dosage of 5 mg/m2 just prior to chemotherapy and every 2–4 hours as needed. Adverse effects include euphoria, dysphoria, sedation, hallucinations, dry mouth, and increased appetite. It has some autonomic effects that may result in tachycardia, conjunctival injection, and orthostatic hypotension. Dronabinol has no significant drug-drug interactions but may potentiate the clinical effects of other psychoactive agents.


Pharmacology_Katzung

Pharmacology_Katzung. Nabilone is a closely related THC analog that has been available in other countries and is now approved for use in the USA. IBD comprises two distinct disorders: ulcerative colitis and Crohn’s disease. The etiology and pathogenesis of these disorders remain unknown. For this reason, pharmacologic treatment of inflammatory bowel disorders often involves drugs that belong to different therapeutic classes and have different but nonspecific mechanisms of anti-inflammatory action. Drugs used in IBD are chosen on the basis of disease severity, responsiveness, and drug toxicity (Figure 62–7). Drugs that contain 5-aminosalicylic acid (5-ASA) have been used successfully for decades in the treatment of IBDs (Figure 62–8). 5-ASA differs from salicylic acid only by the addition of an amino group at the 5 (meta) position. Aminosalicylates are believed to Responsiveness severity to therapy


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 62–7 Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn’s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn’s colitis or Crohn’s perianal disease), or budesonide (Crohn’s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission; immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission; or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids,


Pharmacology_Katzung

Pharmacology_Katzung. to promote or maintain disease remission; or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn’s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs Used in the Treatment of Gastrointestinal Diseases 1107 work topically (not systemically) in areas of diseased gastrointestinal mucosa. Up to 80% of unformulated, aqueous 5-ASA is absorbed from the small intestine and does not reach the distal small bowel or colon in appreciable quantities. To overcome the rapid absorption of 5-ASA from the proximal small intestine, a number of formulations have been designed to deliver 5-ASA to various distal segments of the small bowel or the colon. These include sulfasalazine, olsalazine, balsalazide, and various forms of mesalamine. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Azo compounds—Sulfasalazine, balsalazide, and olsalazine contain 5-ASA bound by an azo (N=N) bond to an inert compound or to another 5-ASA molecule (Figure 62–8). In sulfasalazine, 5-ASA is bound to sulfapyridine; in balsalazide, 5-ASA is bound to 4-aminobenzoyl-β-alanine; and in olsalazine, two 5-ASA molecules are bound together. The azo structure markedly reduces absorption of the parent drug from the small intestine. In the terminal ileum and colon, resident bacteria cleave the azo bond by means of an azoreductase enzyme, releasing the active 5-ASA. Consequently, high concentrations of active drug are made available in the terminal ileum or colon. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Mesalamine compounds—Other proprietary formulations have been designed that package 5-ASA itself in various ways to deliver it to different segments of the small or large bowel. These 5-ASA formulations are known generically as mesalamine. Pentasa is a mesalamine formulation that contains timed-release microgranules that release 5-ASA throughout the small intestine (Figure 62–9). Asacol and Apriso have 5-ASA coated in a pH-sensitive resin that dissolves at pH 6–7 (the pH of the distal ileum and proximal colon). Lialda also uses a pH-dependent resin that encases a multimatrix core. On dissolution of the pH-sensitive resin in the colon, water slowly penetrates its hydrophilic and lipophilic core, leading to slow release of mesalamine throughout FIGURE 62–8 Chemical structures and metabolism of aminosalicylates. Azo compounds (balsalazide, olsalazine, sulfasalazine) are converted by bacterial azoreductase to 5-aminosalicylic acid (mesalamine), the active therapeutic moiety.


Pharmacology_Katzung

Pharmacology_Katzung. Sulfasalazine Balsalazide 5-ASA pH-dependent release (Asacol, Lialda) 5-ASA delayed-release capsules (Pentasa) FIGURE 62–9 Sites of 5-aminosalicylic acid (5-ASA) release from different formulations in the small and large intestines. the colon. 5-ASA also may be delivered in high concentrations to the rectum and sigmoid colon by means of enema formulations (Rowasa) or suppositories (Canasa). Although unformulated 5-ASA is readily absorbed from the small intestine, absorption of 5-ASA from the colon is extremely low. In contrast, approximately 20–30% of 5-ASA from current oral mesalamine formulations is systemically absorbed in the small intestine. Absorbed 5-ASA undergoes N-acetylation in the gut epithelium and liver to a metabolite that does not possess significant anti-inflammatory activity. The acetylated metabolite is excreted by the kidneys.


Pharmacology_Katzung

Pharmacology_Katzung. Of the azo compounds, 10% of sulfasalazine and less than 1% of balsalazide are absorbed as native compounds. After azoreductase breakdown of sulfasalazine, over 85% of the carrier molecule sulfapyridine is absorbed from the colon. Sulfapyridine undergoes hepatic metabolism (including acetylation) followed by renal excretion. By contrast, after azoreductase breakdown of balsalazide, over 70% of the carrier peptide is recovered intact in the feces and only a small amount of systemic absorption occurs.