Only 8 (53%) of these individuals had nocturnal acid breakthrough when receiving omeprazole 20 mg daily, and nocturnal acid breakthrough was not present in any of the 15 subjects when receiving omeprazole 20 mg twice daily. Recording intragastric pH data in 15 asymptomatic H pylori-positive volunteers, Martinek and colleagues reported on the presence of at least 60 continuous minutes of intragastric pH < 4 during nighttime in almost all (93%) H pylori-positive individuals when not taking PPIs. Recent studies have reported on the relationship between H pylori status and presence of nocturnal acid breakthrough. Key: Ome 20 = omeprazole 20 mg (oral) every morning Lanso 30 = lansoprazole 30 mg (oral) every morning Panto 40 = pantoprazole 40 mg (oral) every morning Rabe 20 = rabeprazole 20 mg (oral) every morning. Note the beginning of nocturnal acid breakthrough between 9:00 and 10:00 PM for all PPIs. Twenty-four-hour intragastric pH profiles of daily-dosed PPIs. In subjects taking PPIs once daily before breakfast, the event occurs early in the evening, beginning around 10:00 PM, while in subjects taking PPIs twice daily before breakfast and dinner, nocturnal acid breakthrough occurs 6-7 hours after the evening dose of the PPI (some time between 1:00 and 4:00 AM). The onset of nocturnal acid breakthrough depends on the timing of PPI administration. Nocturnal acid breakthrough was also noted during daily dosing with esomeprazole only 45% of healthy volunteers taking twice-daily esomeprazole 20 mg exhibited nocturnal acid breakthrough. Subsequently, this pharmacologic phenomenon was reported with equal frequency with omeprazole, lansoprazole, rabeprazole, and pantoprazole, and was demonstrated in both healthy subjects and patients with GERD. The study authors analyzed intragastric 24-hour pH profiles in a series of 45 patients treated with PPIs twice daily and identified that it occurred in 70% of patients during the nighttime period. Peghini and colleagues were the first to introduce the term "nocturnal acid breakthrough," and defined it as gastric acid recovery to a pH level < 4 for at least 60 consecutive minutes in the overnight period (10:00 PM to 6:00 AM). Recovery of intragastric acidity, primarily during nighttime while on PPI therapy, should not be regarded as a failure of, or resistance to, these compounds, but rather as an expected phenomenon that may require attention in some patients. Reasons for this phenomenon include the relative short serum half-life of PPIs (2-4 hours), the fact that not all proton pumps are active at the same time, and that generation of new proton pumps is a continuous process. Subsequent clinical data revealed that PPIs, even though they significantly decrease acid secretion, do not completely eliminate intragastric acidity. The concern about iatrogenic achlorhydria and its consequences led to an initial "black box" warning regarding the duration of treatment with PPIs. The initial, basic science reports on the PPIs described these medications as irreversible inhibitors of the proton pump, underscoring the need for synthesis of new proton pumps before acid secretion could be resumed. The introduction of PPIs in the 1980s changed the clinical approach to and management of peptic diseases such as gastric ulcers, duodenal ulcers, and GERD. The H+/K+ ATP-ase responsible for this process is also known as the "proton pump," and is inhibited by substituted benzimidazoles or PPIs. The energy required to transfer protons across the high concentration gradient (intracellular pH is approximately 7 while the intragastric pH is close to 1) comes from cleaving ATP molecules. The final step in gastric acid secretion is the exchange of intracellular protons (H+) for extracellular potassium (K+).
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