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• PROTON PUMP INHIBITORS

The proton pump inhibitors were first introduced in 1989 with omeprazole (Prilosec®). Since then, there have been four additional oral agents added to the market: lansoprazole (Prevacid®) in 1995, rabeprazole (Aciphex®) in 1999, pantoprazole oral (Protonix®) in 2000 and esomeprazole (Nexium®), the isomer of omeprazole, in 2001. In addition, pantoprazole is available as an intravenous product. Other intravenous products are in the pipeline. All of these agents are prescription products.18,19,20, 21,22 Recently, the FDA approved omeprazole for a switch to an over-the-counter status.23

 

All of the proton pump inhibitors have a similar mechanism of action. Once absorbed, the proton pump inhibitors are trapped in the acidic media of the canicular space of the parietal cell. Concentration of the proton pump inhibitor may be up to 1,000-fold higher on luminal side of secretory canaliculus.11,24 In the acid media, the proton pump inhibitor is protonated to the active sulfenamide. The proton pump inhibitor then binds irreversibly to a cyteine residue on the expressed actively secreting H+/K+ ATPase pump. The different proton pump inhibitors bind to different cysteine residue; however, the clinical relevance of these different binding sites is not yet known.11

 

Given the need for protonation of these agents, the pKa becomes a relevant issue. The pKa is the pH when 50 percent of the drug is protonated. The pKa of these agents are 3.8 for pantoprazole, 3.9 for lansoprazole, 4 for omeprazole and esomeprazole and 5 for rabeprazole. At a pH of 1.2, all of these agents have a short activation half-life (pantoprazole 4.6 minutes, lansoprazole 2 minutes, omeprazole 2.8 minutes and rabeprazole 1.3 minutes). However, at a pH higher than the drugs’ pKa, there is a decrease in the amount of protonated drug. Therefore, at a pH of 5.1, the activation half-lives are increased (pantoprazole 282 minutes, lansoprazole 90 minutes, omeprazole 80 minutes and rabeprazole 7.2 minutes).24 The clinical relevance of this is still being elucidated; however, this may lead to faster pH control and symptom relief.

 

Esomeprazole is the S-isomer of omeprazole. Although both isomers of omeprazole are active, the S-isomer is metabolized slower than the R-isomer. The different pharmacokinetics of esomeprazole may increase the effectiveness compared with omeprazole.21

 

Acid effect.
All of the proton pump inhibitors have a demonstrated effect on reducing acid secretion, even on day one. In a study by Williams et al.,25 rabeprazole 20 mg and omeprazole 20 mg significantly reduced intragastric acidity over the course of 24 hours compared with placebo in 24 H. pylori negative healthy subjects on day one. In addition, the reduction with rabeprazole was significantly greater than omeprazole (acidity: rabeprazole 331 vs. omeprazole 640 mmol.h/L, p < 0.001). By day eight, both agents still significantly reduced the acidity with rabeprazole still having a larger reduction; however, the difference was not statistically significant. With omeprazole and placebo, there was an increase in intragastric acidity associated with meals, but this response was not seen with rabeprazole. The amount of time the pH was greater than 4 on day eight was 60 percent for rabeprazole and 51 percent for omeprazole (p = 0.03). All three treatment groups had an increase in intragastric acidity overnight, though the increase was significantly less with omeprazole and rabeprazole than with placebo. The overall reduction in intragastric acidity on day one compared with maximal effect as seen on day eight was 88 percent with rabeprazole and 42 percent with omeprazole.

 

In numerous studies comparing the time pH is greater than 4 with the proton pump inhibitors, there are significant differences in proton pump inhibitors on day one. However, by the end of the week, there usually is no difference noted. In the findings of Williams et al., on day one, the pH was greater than 4 with rabeprazole 20 mg 44.1 percent of the time and 24.7 percent of the day with omeprazole 20 mg day treated patients. By day eight, the pH was greater than 4 for 60.3 percent and 51.4 percent, respectively.25

 

When looking at meal stimulated acid secretion on day one, there was no significant difference among omeprazole, pantoprazole and placebo. However, by day three and day five, there was a significant decrease in meal-stimulated acid secretion with omeprazole and pantoprazole compared with placebo.26

 

In a six-way crossover study, Pantoflickova et al.27 evaluated the median intragastric pH on day one in 18 H. pylori-negative healthy subjects on rabeprazole, lansoprazole, pantoprazole, omeprazole capsules, omeprazole multiple unit pellet system (MUPS) and placebo. Rabeprazole-treated patients had a median intragastric pH of 3.4, significantly higher than all the other agents (p ≤ 0.03). Lansoprazole-treated patients had a median intragastric pH of 2.9, significantly higher than the other agents with exception of rabeprazole (p ≤ 0.01). Pantoprazole-treated patients had a median intragastric pH of 2.2, omeprazole-treated patients, 1.9; MUPS-treated patients 1.8 and placebo-treated patients, 1.3. Rabeprazole, lansoprazole and pantoprazole maintained the acid-inhibiting effects during the night when compared with placebo. Rabeprazole maintained a significantly higher pH value during the nighttime period compared with the other agents. Overall, this study supports the hypothesis that the higher pKa of rabeprazole may impart faster onset of action.

 

Florent et al.28 evaluated the median daytime and nighttime pH values on day one and seven between lansoprazole and pantoprazole. On day one, the median daytime pH was 4.55 for lansoprazole and 2.18 for pantoprazole compared with 1.55 for the basal time frame (p = 0.003 lansoprazole vs. pantoprazole). The day one median nighttime pH was 2.88 for lansoprazole, 1.94 for pantoprazole and 1.4 for basal (p = 0.0025 lansoprazole vs. pantoprazole). By day seven, differences between lansoprazole and pantoprazole were no longer significant, with median daytime pH of 4.75 and 3.5 and median nighttime pH of 3.09 and 2.72, respectively. When comparing the median percentage of time that pH was greater than 4, on day one lansoprazole was 51 percent (p ≤ 0.008 vs baseline) and pantoprazole was 23 percent (p ≤ 0.02 vs. baseline); by day seven, lansoprazole was 49 percent (p ≤ 0.008 versus baseline) and pantoprazole was 34 percent (p ≤ 0.02 versus baseline). Looking at mean percentage of time above pH 4, there was no difference on day one or day seven with lansoprazole (44 percent each day); however, pantoprazole increased from 24 percent on day one to 32 percent by day seven. Overall, this study supports similar effects of lansoprazole and pantoprazole by day seven. However, lansoprazole produced more significant pH effects on day one compared with pantoprazole.

 

Hartman et al.29 compared the median pH for 24 hours, daytime (0900 – 2300) and nighttime (2300-0600) in patients receiving pantoprazole 40 mg, omeprazole 20 mg or placebo in a crossover study in 16 healthy male subjects. On day one, the median 24 hour pH for pantoprazole treated patients was 1.45 compared with 1.3 for omeprazole-treated patients (p < 0.01) and 1.2 for placebo-treated patients. The daytime median pH on day one was 1.6 for pantoprazole-treated patients and 1.3 for omeprazole treated patients (p < 0.01) and 1.4 for placebo treated patients. There were no differences among the nighttime median pH with 1.2, 1.1, and 1.0 respectively. On day seven, the median 24 hour pH was 3.15 for pantoprazole-treated patients and 2.05 for omeprazole-treated patients (p < 0.01). The median daytime pH was 3.8 for pantoprazole-treated patients and 2.65 for omeprazole-treated patients (p < 0.05); and the median nighttime pH was 1.5 for pantoprazole treated patients and 1.4 for omeprazole-treated patients.

 

Robinson et al.30 compared the acid suppression of rabeprazole 20 mg and 40 mg in 20 patients with GERD in a two-way crossover study. By day seven, acid exposure decreased by 79 percent in rabeprazole 20 mg-treated patients and 92 percent in rabeprazole 40 mg-treated patients. The mean gastric pH increased from a baseline of 1.86 to 3.71 on day one and 4.17 on day seven with rabeprazole 20 mg and from a baseline of 2.01 to 4.37 on day one and 4.65 on day seven with rabeprazole 40 mg (p < 0.001 versus baseline).

 

Lind et al.31 evaluated the antisecretory effects of esomeprazole and omeprazole on day five in 38 patients with symptoms of GERD in a double-blind randomized crossover study. The 24 hour median intragastric pH was 4.9 for esomeprazole 40 mg-treated patients, 4.1 for esomeprazole 20 mg-treated patients and 3.6 for omeprazole 20 mg-treated patients (p < 0.01 for esomeprazole 40 mg versus 20 mg or placebo and esomeprazole 20 mg versus placebo). The percentage of time that the pH was greater than 4 was 69.8 percent with esomeprazole 40 mg, 53 percent for esomeprazole 20 mg and 43.7 percent for omeprazole 20 mg (p < 0.01 for esomeprazole 40 mg versus 20 mg or placebo and esomeprazole 20 mg versus placebo). Overall, esomeprazole has a greater effect on pH than omeprazole.

 

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