Page 1107 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 62 Drugs Used in the Treatment of Gastrointestinal Diseases 1093

liver disease but should be considered in patients with severe liver In current clinical practice, many patients with symptomatic
impairment. Although other proton pumps exist in the body, GERD are treated empirically with medications without prior
+
+
the H /K -ATPase appears to exist only in the parietal cell and is endoscopy, ie, without knowledge of whether the patient has
+
distinct structurally and functionally from other H -transporting erosive or nonerosive reflux disease. Empiric treatment with PPIs
enzymes. provides sustained symptomatic relief in 70–80% of patients,
The intravenous formulations of esomeprazole and pantopra- compared with 50–60% with H antagonists. Because of recent
2
zole have characteristics similar to those of the oral drugs. When cost reductions, PPIs are used increasingly as first-line therapy for
given to a fasting patient, they inactivate acid pumps that are patients with symptomatic GERD. Due to recent safety concerns,
actively secreting, but they have no effect on pumps in quiescent, however, initial empiric treatment with an H antagonist should
2
nonsecreting vesicles. Because the half-life of a single injection of be considered.
the intravenous formulation is short, acid secretion returns several Sustained acid suppression with twice-daily PPIs for at least
hours later as pumps move from the tubulovesicles to the canalicu- 3 months is used to treat extraesophageal complications of reflux
lar surface. Thus, to provide maximal inhibition during the first disease (asthma, chronic cough, laryngitis, and noncardiac chest
24–48 hours of treatment, the intravenous formulations must be pain).
given as a continuous infusion or as repeated bolus injections. The
optimal dosing of intravenous PPIs to achieve maximal blockade 2. Peptic ulcer disease—Compared with H antagonists, PPIs
2
in fasting patients is not yet established. afford more rapid symptom relief and faster ulcer healing for duo-
From a pharmacokinetic perspective, PPIs are ideal drugs: they denal ulcers and, to a lesser extent, gastric ulcers. All the pump
have a short serum half-life, they are concentrated and activated inhibitors heal more than 90% of duodenal ulcers within 4 weeks
near their site of action, and they have a long duration of action. and a similar percentage of gastric ulcers within 6–8 weeks.
a. H pylori-associated ulcers—For H pylori-associated ulcers,
Pharmacodynamics there are two therapeutic goals: to heal the ulcer and to eradicate

In contrast to H antagonists, PPIs inhibit both fasting and the organism. The most effective regimens for H pylori eradica-
2
meal-stimulated secretion because they block the final common tion are combinations of two antibiotics and a PPI. PPIs pro-
pathway of acid secretion, the proton pump. In standard doses, mote eradication of H pylori through several mechanisms: direct
PPIs inhibit 90–98% of 24-hour acid secretion (Figure 62–2). antimicrobial properties (minor) and—by raising intragastric
When administered at equivalent doses, the different agents pH—lowering the minimal inhibitory concentrations of antibiot-
show little difference in clinical efficacy. In a crossover study of ics against H pylori. Until recently, the most commonly recom-
patients receiving long-term therapy with five PPIs, the mean mended treatment regimen consisted of a 14-day regimen of
24-hour intragastric pH varied from 3.3 (pantoprazole, 40 mg) “triple therapy”: a PPI twice daily; clarithromycin, 500 mg twice
to 4.0 (esomeprazole, 40 mg), and the mean number of hours the daily; and either amoxicillin, 1 g twice daily, or metronidazole,
pH was higher than 4 varied from 10.1 (pantoprazole, 40 mg) 500 mg twice daily. Due to increasing treatment failures attribut-
to 14.0 (esomeprazole, 40 mg). Although dexlansoprazole has able to rising clarithromycin resistance, “quadruple therapy” is
a delayed-release formulation that results in a longer T and now recommended as first-line treatment for patients who likely
max
greater AUC than other PPIs, it appears comparable to other have clarithromycin resistance due to prior exposure or to resi-
agents in the ability to suppress acid secretion. This is because dence in regions with high clarithromycin resistance. Two 14-day
acid suppression is more dependent upon irreversible inactiva- treatment regimens currently are recommended. Each includes
tion of the proton pump than the pharmacokinetics of different a PPI twice daily with either: (a) bismuth subsalicylate 524 mg,
agents. metronidazole 500 mg, and tetracycline 500 mg, all given four
times daily; or (b) amoxicillin 1 g, clarithromycin 500 mg, and
Clinical Uses metronidazole 500 mg, all given twice daily. After completion of
antibiotic therapy, the PPI should be continued once daily for a
1. Gastroesophageal reflux disease—PPIs are the most total of 4–6 weeks to ensure complete ulcer healing.
effective agents for the treatment of erosive reflux disease, esopha-
geal complications of reflux disease (peptic stricture or Barrett’s b. NSAID-associated ulcers—For patients with ulcers caused
esophagus), and extraesophageal manifestations of reflux disease. by aspirin or other NSAIDs, either H antagonists or PPIs pro-
2
Once-daily dosing provides effective symptom relief and tissue vide rapid ulcer healing so long as the NSAID is discontinued;
healing in 85–90% of patients; up to 15% of patients require however, continued use of the NSAID impairs ulcer healing.
twice-daily dosing. In patients with NSAID-induced ulcers who require continued
GERD symptoms recur in over 80% of patients within NSAID therapy, treatment with a PPI more reliably promotes
6 months after discontinuation of a PPI. For patients with erosive ulcer healing.
esophagitis or esophageal complications, long-term daily mainte- Asymptomatic peptic ulceration develops in 10–20% of people
nance therapy with a full-dose or half-dose PPI is usually needed. taking frequent NSAIDs, and ulcer-related complications (bleed-
Many patients with nonerosive GERD may be treated success- ing, perforation) develop in 1–2% of persons per year. PPIs taken
antagonists taken as once daily are effective in reducing the incidence of ulcers and
fully with intermittent courses of PPIs or H 2
needed (“on demand”) for recurrent symptoms. ulcer complications in patients taking aspirin or other NSAIDs.