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Management of GERD: Prescription Therapies

Proton pump inhibitors (PPIs)

Management of GERD: Prescription TherapiesPrescription therapies aimed at reducing acid secretion in patients with gastroesophageal reflux disease (GERD) are H2RAs and PPIs. Ample clinical evidence supports the superiority of acid suppression with proton pump inhibitors (PPIs) over other agents.A meta-analysis of 33 trials in over 3,000 patients revealed that symptomatic relief can be expected in 27% of placebo-treated, 60% of H2RA-treated, and 83% of PPI-treated patients. Esophagitis was healed in 24% of patients given placebo, 50% of those given H2RA, and 78% of patients given PPIs. PPIs eliminate symptoms and heal esophagitis more frequently and more rapidly than the other agents. Studies suggest that in order to achieve maximal healing of the esophageal mucosa, pH higher than 4.0 must be maintained for at least 18 hours per day. In one study, 24-hour pH monitoring demonstrated that omeprazole 20 to 40 mg/day maintained pH above 4.0 for 15 to 21 hours, compared to four hours with cimetidine 400 mg four times daily, and nine hours with ranitidine 300 mg per day.Following initial healing of esophagitis, recurrence is common, with rates of 50% to 80% without maintenance therapy. Maintenance therapy with daily proton pump inhibitors (PPIs) reduces recurrence rates to 1% to 30% over one year, while H2RAs are associated with higher recurrence rates of 68% to 88%. Clinical practice guidelines recommend the use of PPIs as initial treatment of gastroesophageal reflux disease (GERD) and emphasize that many patients require continuous maintenance therapy with proton pump inhibitors (PPIs) to adequately control their disease.

Pharmacology of proton pump inhibitors (PPIs): Currently, five proton pump inhibitors are available on the market: esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (Aciphex). All require activation to irreversibly inhibit the gastric proton pump (H/K-ATPase). Due to irreversible inhibition, recovery of proton pump activity requires the synthesis of new H/K-ATPase, which takes 96 hours in humans. However, nearly 25% of proton pumps are replaced daily; therefore, achlorhydria is never achieved with PPI therapy. All proton pump inhibitors (PPIs) are weak bases that are ionized and activated at an acidic pH. Due to their acid lability, PPIs are enteric-coated to ensure maximum bioavailability. Because proton pump inhibitors (PPIs) bind only to actively secreting proton pumps, it is best to take them 30 to 60 minutes before a meal. PPIs have demonstrated a potent antisecretory effect that is sustained for a prolonged period of time due to the irreversible nature of pump inhibition. Pharmacokinetic features of proton pump inhibitors (PPIs) are compared in TABLE 2. All share similar pharmacokinetic profiles; the most notable differences are seen in their drug interaction potential (TABLE 3).

Table 2. Pharmacokinetic Features of proton pump inhibitors (PPIs)
  Omeprazole
(Prilosec)
Lansoprazole
(Prevacid)
Rabeprazole
(Aciphex)
Pantoprazole
(Protonix)
Esomeprazole
(Nexium)
Dose (mg) 20 30 20 40 40

Cmax (mmol/L) 1.1 2.2 1.1 5.6 4.7

Tmax (h) 0.5
to 3.5
1.7 2.0
to 5.0
2.5 1.6

AUC0-24 (mmol*hr/mL) 1.1 5.0 2.1 11.1 4.3

Total clearance (L/h) 30.0 to 36.0 49.0 16.8 to 33.6 7.6 to 14.0 9.0 to 16.0

Absolute bioavailability (%) 30 to 40 80 52 77 90

Protein binding (%) 95 97 96 98 97

Table 3. Cytochrome P-450 Activity and Drug Interactions of PPIs
  Omeprazole
(Prilosec)
Lansoprazole
(Prevacid)
Rabeprazole
(Aciphex)
Pantoprazole
(Protonix)
Esomeprazole
(Nexium)
Primary Pathway CYP2C19 CYP3A4 CYP2C19 CYP2C19 CYP2C19

Secondary pathway(s) CYP3A4 CYP2C19 CYP3A4 CYP3A4,
2D6, 2C9
CYP3A4

Active Metabolites No Yes No No No

Significant drug interactions* Diazepam, warfarin, phenytoin, cyclosporin, disulfiram, clarithromycin None Warfarin, cyclosporin None Warfarin, diazepam

* All proton pump inhibitors (PPIs) decrease absorption of drugs that require acidic gastric pH for optimal absorption (eg, ketoconazole, iron salts, digoxin).

Relative Efficacy of proton pump inhibitors (PPIs)

PPIs have been proven to produce symptom relief and healing of esophageal erosion for patients with gastroesophageal reflux disease (GERD). All are approved for the treatment of acute esophagitis, maintenance therapy of esophagitis, and symptomatic GERD (except for pantoprazole; TABLE 4). Most investigators have found similar efficacy among different proton pump inhibitors (PPIs). Several clinical trials, however, suggest that during the first week of treatment, lansoprazole 30 mg/day provides earlier symptom relief than omeprazole 20 mg/day. Recently, two multicenter, double-blind, randomized studies showed that esomeprazole 40 mg/day produced higher esophageal healing rates than omeprazole 20 mg/day after four and eight weeks of treatment. Patients receiving esomeprazole also had faster and more sustained symptom relief. Two other studies, however, failed to demonstrate any significant differences between esomeprazole 40 mg/day and omeprazole 20 mg/day and between esomeprazole 20 mg/day and omeprazole 20 mg/day.

Another study compared the extent of acid suppression with rabeprazole 20 mg versus omeprazole 20 mg. On the first day, rabeprazole maintained a gastric pH higher than 4.0 for an average of 44.1% of the day while omeprazole did the same for 24.7% of the day. By day 8 of the study, the extent of acid suppression with rabeprazole was still significantly higher than that with omeprazole (60.3% vs 50.4% of the day with pH > 4.0, respectively; P =.03). No studies directly compare esomeprazole with rabeprazole and pantoprazole.

Esomeprazole 40 mg/day was also compared to lansoprazole 30 mg/day in patients with endoscopically verified erosive esophagitis. Patients receiving esomeprazole had significantly greater relief of daytime and nocturnal symptoms than those receiving lansoprazole and achieved significantly higher esophageal healing rates at week 8 (92.6% vs 88.8%, P = .0001). The difference in cumulative healing rates was more pronounced in patients with a more severe degree of esophagitis. It is important to note, however, that a difference in healing rates of less than 4% may not be clinically significant. A recent randomized, double-blind, controlled, head-to-head study of lansoprazole 30 mg/day and esomeprazole 40 mg/day showed similar effectiveness in healing esophageal erosions and relieving heartburn. These apparently conflicting findings from numerous trials can be explained in part by differences in study designs as well as the use of proton pump inhibitors (PPIs) at doses that are not equipotent. Some studies were performed in healthy volunteers and no clinical end points were measured; therefore, it is difficult to apply the results of such studies to the clinical setting. Until more data become available, guidelines recommend any of the available PPIs for treatment of gastroesophageal reflux disease (GERD).

The safety profile of proton pump inhibitors (PPIs) is excellent. Headache and diarrhea are the most common side effects reported with short-term use. There is a concern, however, that chronic use of PPIs can lead to increases in serum gastrin concentrations because of acid inhibition. In rat models, prolonged hypergastrinemia is associated with enterochromaffin-like cell hyperplasia and carcinoid tumors. However, long-term follow-up studies and more than a decade of clinical experience lack evidence that the use of proton pump inhibitors (PPIs) can result in long-term complications. PPIs improve health-related quality of life (HRQOL) in patients with gastroesophageal reflux disease (GERD) with or without esophagitis and result in a more significant improvement than H2RAs or cisapride. The studies mentioned above have demonstrated that HRQOL response to treatment is independent of esophagitis and that the impact on health-related quality of life (HRQOL) is proportional to symptom improvement.

Table 4. FDA-Labeled Indications and Dosage Regimens of PPIs
  Omeprazole
(Prilosec)
Lansoprazole
(Prevacid)
Rabeprazole
(Aciphex)
Pantoprazole
(Protonix)
Esomeprazole
(Nexium)
Symptomatic GERD (4 weeks*) 20 mg 15 mg 20 mg No indication 20 mg

Acute esophagitis (8 weeks**) 20 mg 30 mg 20 mg 40 mg 20-40 mg

Maintenance esophagitis
(as long as indicated)
20 mg 15 mg 20 mg 40 mg 20 mg

* If symptoms do not resolve after four weeks, an additional course of treatment may be considered.** If complete healing is not achieved after eight weeks, an additional eight weeks of therapy may be considered.

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