In: Main13 Apr 2010
PROTON PUMP INHIBITORS: AN OVERVIEW
Acid-related disorders encompass a wide variety of diagnoses, including the extremely prevalent gastroesophageal reflux disease (GERD), which affects an estimated 25 million Americans, duodenal and gastric ulceration, stress-related mucosal disease, and acute upper gastrointestinal bleeding, a common medical emergency resulting in approximately 300,000 hospitalizations annu-ally. During the last three decades, the management of these disorders has been revolutionized by the introduction of his-tamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs).
Five available delayed-release PPIs include omeprazole (Astra-Zeneca), generic lansoprazole (TAP, Wyeth), magnesium (Astra-Zeneca), and (Eisai/Janssen). These drugs are highly effective, irreversible inhibitors of H+/K+ ATPase, the final step in gastric acid secretion.
Although these agents form the therapeutic cornerstone of management for a variety of acid-related disorders, there is still room for improvement in our armamentarium. For example, all PPI compounds are weak bases that are acid-labile and are rapidly degraded, usually within minutes, in the acidic environment of the stomach. Until the recent introduction of immediate-release (IR-OME [Zegerid, Santarus]), this pharmacological property required the active ingredient in all delayed-release oral PPI formulations to have an enteric coating. The coating protects the active ingredient from degradation by gastric acid, but it also delays absorption, so that the peak plasma concentration (Cmax) is not typically attained for up to five hours after oral administration of these formulations. In addition, patients must not chew or crush the tablets or the enteric-coated granules.
For patients who cannot swallow intact capsules or tablets or who have a nasogastric tube in place, various liquid formulations have been compounded extemporaneously from sodium bicarbonate solution, with omeprazole canadian or lanso-prazole granules, or crushed panto-prazole tablets. These formulations have a limited shelf life and may adhere to the syringe and the tubing used for administration, with the result that the tubing has the potential to become clogged.
Limitations to enteric-coated PPI formulations also include the potential for nocturnal acid breakthrough (NAB), defined as an intragastric pH below 4 for at least one hour during the night with PPI therapy. NAB occurs in up to 70% of patients with GERD. Despite adequate therapeutic dosing (including twice-daily administration), patients taking enteric-coated, delayed-release PPIs may experience nocturnal gastric acidity, whether or not the agent is taken before breakfast, before dinner, or twice daily and may have nighttime symptoms of heartburn. Patients with nocturnal GERD may have a higher potential for severe reflux-induced complications such as esophagi-tis, Barrett’s esophagus, esophageal motility disorder, esophageal stricture formation, and esophageal adeno-carcinoma. Individuals with nocturnal heartburn also report less satisfaction with PPIs and a diminished quality of life in terms of both mental and physical components, compared with GERD patients, who do not experience nocturnal heartburn.
Strategies for managing nocturnal gastric acidity include increasing PPI administration from once to twice daily, increasing the dose, switching to another PPI, or adding an H2RA at bedtime. Although this last strategy may provide short-term efficacy, its clinical utility may be limited by the potential for the development of tolerance to H2RAs as well as by the additional cost of therapy.
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Lapses in controlling gastric pH during PPI therapy may impair the ability of PPIs to adequately protect against stress-related intestinal mucosal disease, a significant clinical problem that occurs in 70% to 90% of critically ill patients and portends increased morbidity as well as extended hospital stays. Among patients who are not given prophylactic pharmacological therapy, overt upper gastrointestinal (GI) bleeding has been documented in 17% of critically ill patients.
More than a decade ago, investigators found that various degrees of acid suppression produced different physiological effects in the gastric milieu. At a pH of 4.5 or above, pepsin begins to be inactivated; at a pH of 5 or above, it becomes completely inactivated; and at a pH of 7 or above, there is a potential for a decreased incidence of peptic ulcer rebleeding in patients who have already achieved hemostasis.
Some investigators suggest that a gastric pH of 6.5 or higher is optimal for preventing stress ulceration; at this value, pepsin is inactivated and blood coagulation parameters are maintained, although other authors consider a pH of 3.5 to 4 or above to be sufficient. H2RAs can be effective in attaining these levels, but tachyphylaxis is a frequent occurrence. More recent studies support the clinical efficacy of PPI therapy in the management of these critically ill patients; a recent Cochrane Collaboration found that the ability of PPI therapy to raise gastric pH is independent of the route of administration; however, this effect must be sustainable.
Therefore, although significant progress has been made in treating acid-related disorders, patients would benefit from advances in PPI therapy. Specifically, an acid-suppressing agent that shows more rapid absorption; that can be administered orally, even in patients who cannot swallow intact capsules or tablets; that provides better nocturnal acid control; and that sustains gastric pH above a critical threshold would be a welcome addition to the PPI class.
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