Page 1109 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 62 Drugs Used in the Treatment of Gastrointestinal Diseases 1095

long time also may exhibit ECL hyperplasia, carcinoid tumor for- in which the pH ranges from 7 at the mucosal surface to 1–2
mation has not been documented. At present, routine monitoring in the gastric lumen. Blood flow carries bicarbonate and vital
of serum gastrin levels is not recommended in patients receiving nutrients to surface cells. Areas of injured epithelium are quickly
prolonged PPI therapy. repaired by restitution, a process in which migration of cells
from gland neck cells seals small erosions to reestablish intact
5. Other potential problems due to decreased gastric epithelium. Mucosal prostaglandins appear to be important in
acidity—Among patients infected with H pylori, long-term stimulating mucus and bicarbonate secretion and mucosal blood
acid suppression leads to increased chronic inflammation in the flow. A number of agents that potentiate these mucosal defense
gastric body and decreased inflammation in the antrum. Con- mechanisms are available for the prevention and treatment of
cerns have been raised that increased gastric inflammation may acid-peptic disorders.
accelerate gastric gland atrophy (atrophic gastritis) and intestinal
metaplasia—known risk factors for gastric adenocarcinoma. A
special FDA Gastrointestinal Advisory Committee concluded SUCRALFATE
that there is no evidence that prolonged PPI therapy produces
the kind of atrophic gastritis (multifocal atrophic gastritis) or Chemistry & Pharmacokinetics
intestinal metaplasia that is associated with increased risk of
adenocarcinoma. Routine testing for H pylori is not recom- Sucralfate is a salt of sucrose complexed to sulfated aluminum
mended in patients who require long-term PPI therapy. Long- hydroxide. In water or acidic solutions it forms a viscous, tena-
term PPI therapy is associated with the development of small cious paste that binds selectively to ulcers or erosions for up to
benign gastric fundic-gland polyps in a small number of patients, 6 hours. Sucralfate has limited solubility, breaking down into
which may disappear after stopping the drug and are of uncertain sucrose sulfate (strongly negatively charged) and an aluminum
clinical significance. salt. Less than 3% of intact drug and aluminum is absorbed from
the intestinal tract; the remainder is excreted in the feces.
Drug Interactions
Decreased gastric acidity may alter absorption of drugs for which Pharmacodynamics
intragastric acidity affects drug bioavailability, eg, ketoconazole, A variety of beneficial effects have been attributed to sucralfate,
itraconazole, digoxin, and atazanavir. All PPIs are metabolized by but the precise mechanism of action is unclear. It is believed that
hepatic P450 cytochromes, including CYP2C19 and CYP3A4. the negatively charged sucrose sulfate binds to positively charged
Because of the short half-lives of PPIs, clinically significant drug proteins in the base of ulcers or erosion, forming a physical bar-
interactions are rare. Omeprazole may inhibit the metabolism of rier that restricts further caustic damage and stimulates mucosal
clopidogrel, warfarin, diazepam, and phenytoin. Esomeprazole prostaglandin and bicarbonate secretion.
also may decrease metabolism of diazepam. Lansoprazole may
enhance clearance of theophylline. Rabeprazole and pantoprazole Clinical Uses
have no significant drug interactions.
The FDA has issued a warning about a potentially important Sucralfate is administered in a dosage of 1 g four times daily on an
adverse interaction between clopidogrel and PPIs. Clopido- empty stomach (at least 1 hour before meals). At present, its clini-
grel is a prodrug that requires activation by the hepatic P450 cal uses are limited. Sucralfate (administered as a slurry through
CYP2C19 isoenzyme, which also is involved to varying degrees a nasogastric tube) reduces the incidence of clinically significant
in the metabolism of PPIs (especially omeprazole, esomeprazole, upper gastrointestinal bleeding in critically ill patients hospitalized
lansoprazole, and dexlansoprazole). Thus, PPIs could reduce in the intensive care unit, although it is slightly less effective than
clopidogrel activation (and its antiplatelet action) in some intravenous H antagonists. Sucralfate is still used by many clini-
2
patients. Several large retrospective studies have reported an cians for prevention of stress-related bleeding because of concerns
increased incidence of serious cardiovascular events in patients that acid inhibitory therapies (antacids, H antagonists, and PPIs)
2
taking clopidogrel and a PPI. In contrast, three smaller prospec- may increase the risk of nosocomial pneumonia.
tive randomized trials have not detected an increased risk. When
PPIs are prescribed to patients taking clopidogrel, agents with Adverse Effects
minimal CYP2C19 inhibition (pantoprazole or rabeprazole) Because it is not absorbed, sucralfate is virtually devoid of systemic
may be preferred. adverse effects. Constipation occurs in 2% of patients due to the
aluminum salt. Because a small amount of aluminum is absorbed,
MUCOSAL PROTECTIVE AGENTS it should not be used for prolonged periods in patients with renal
insufficiency.
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 Drug Interactions
restrict back diffusion of acid and pepsin. Epithelial bicarbon- Sucralfate may bind to other medications, impairing their
ate secretion establishes a pH gradient within the mucous layer absorption.