P. 1
Antacids

Antacids

|Views: 27|Likes:
Published by amanysalama5976

More info:

Published by: amanysalama5976 on Dec 24, 2011
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

05/28/2012

pdf

text

original

20

Gastric Acid Secretions, Treatments, and Nutritional Consequences
Ronit Zilberboim and Adrianne Bendich

Key Points
• Gastric acid provides an important selective advantage today as when vertebrates evolved. With the eradication of one acid-related gastrointestinal (GI) disease there may be an increase in the incidence of another acid-related GI disease, demonstrating the importance of acid balance. • Certain gastroesophageal diseases require chronic acid-suppressive therapy. • Nutritional intervention at the initiation of acid-suppressive therapy could prevent adverse nutritional consequences. • The effect of acid-suppressive therapy on both vitamin and mineral status is observed only after many years of therapy and recent clinical evidence is available to demonstrate such effects. • Although the use of proton pump inhibitors (PPI) for the diagnosis and treatment of gastrointestinal disorders is effective, step-down strategies for acid-suppressive therapies should be developed and explored in support of updated indication.

Key Words: Achlorhydria; acid-suppression therapies; calcium and iron metabolism; community-acquired pneumonia; gastric secretions; gastroesophageal reflux disease; Helicobacter pylori; histamine receptor antagonists; vitamin B12 ; proton pump inhibitors

20.1. INTRODUCTION
The objectives of this chapter are to provide an overview of the roles of gastric acid in health and disease, the use of acid-suppressive therapies to mitigate prevalent excess acid symptoms and/or diseases, and to review potential detrimental consequences related to their use. Particular emphasis is placed on the nutritional consequences of gastric acid imbalance as it is related to vitamin and mineral status. Finally, reduced gastric acid is also associated with disturbance in the natural bacterial balance throughout the gastrointestinal tract and the resulting gastrointestinal bacterial overgrowth is reviewed.

20.2. GASTRIC ACID
Gastric acid secretion is believed to have developed in the evolution of vertebrates and to provide selective advantages. Acid balance in the stomach is precisely regulated as acid is needed to facilitate digestion and absorption on one hand while too much acid can damage the mucosa and cause ulcers. Stomach acid aids in protein digestion and is thought to be involved in the absorption of minerals such as calcium and iron, as well as vitamins such as B12 . In addition, acid in the stomach has a central role in prevention of bacterial overgrowth and therefore protection against enteric infection. Gastric acid is also involved in upper GI motility and finally may modulate feeding behavior (1,2).

A. Bendich, R.J. Deckelbaum (eds.), Preventive Nutrition, Nutrition and Health, DOI 10.1007/978-1-60327-542-2_20, C Humana Press, a part of Springer Science+Business Media, LLC 1997, 2001, 2005, 2010

471

472

Part V / Prevention of Major Disabilities; Improvement in Health Outcomes

20.2.1. Regulation and Secretion of Gastric Acid
The stomach is organized as vertical tubules and contains two functional elements, the oxyntic and pyloric glands (Fig. 20.1). The oxyntic and pyloric glands are organized in the stomach in three areas: the fundus, corpus, and the antrum. The oxyntic gland is located in the fundus and the corpus which consists of the majority of the stomach’s area (80%). The remaining section of the stomach (20%), the antrum, is covered with the pyloric gland. In terms of acid secretion, the parietal cells which are located only in the fundus and the corpus area secrete acid via the hydrogen potassium adenosine triphosphatase pump (H+ K+ ATPase/ATPase), also known as the proton pump. The pyloric area contains gastrin cells (also called G cells) which produce gastrin, a gastric acid secretion stimulator. D cells, that secrete somatostatin, the main inhibitor of acid secretion, are located throughout the stomach both on oxyntic and pyloric glands. Enterochromaffin-like (ECL) cells secrete histamine and are only located in the oxyntic area. It is estimated that human stomach contains 1 × 109 parietal cells and 9 × 106 gastrin cells (1).

Lumen of the stomach Oxyntic

Enterochromaffin-like cell (Histamine) Esophagus Parietal Cell (Proton pump) Fundus Stomach D cells (Somatostatin) Lumen of the stomach Pylorus Antrum

Pyloric

Duodenum D cells (Somatostatin) G Cells (Gastrin)

Fig. 20.1 Stomach anatomy gastric acid production and functional elements of the stomach’s mucosa.

A detailed review of the early signaling events that ultimately result in acid secretion by parietal cells. G ASTROESOPHAGEAL R EFLUX D ISEASE (GERD) Gastroesophageal reflux disease (GERD) was defined by the Montreal consensus as “a condition which develops when the reflux of the stomach content causes troublesome symptoms and/or complications” (5). GERD is most prevalent in North America and in Europe and between 10 and 29% of adults have this disease (8). The ATPase pump transforms from a sequestered state in the inactive cytoplasmic tubulovesicles to a docking stage followed by priming and fusion with the apical plasma membrane where it is in the active state. This definition is accepted as the operational definition for GERD by the American Gastroenterological Association (AGA) (6). and biological agents. Peripherally. gastric acid secretion is regulated via hormonal.2. and certain types of gastric ulcer.and hyposecretion. Reflux disease is one of the most frequent disorder seen in primary care. GERD tends to be chronic.8. recycling of the proton pump and the role of the cytoskeleton in support of the active acid secretion can be found in Yao and Forte (4). that while about 15% of those surveyed typically experience heartburn for less than 1 year. their prevalence. hypersecretion and hyposecretion have been reported (1). as well as in secondary referral centers and therefore has a high economic impact (9). it was estimated. physiological processes that include exocytosis of the tubulovesicle followed by endocytosis after the termination must occur. While hyposecretion is observed in atrophic and autoimmune gastritis. based on a survey of 1. Importantly. Diseases of Gastric Acid Secretion Several diseases disturb gastric secretions and both over. and acetylcholine (neurocrine).1.1 summarizes diseases associated with both hyper. GERD affects the esophagus primarily. histamine (paracrine). Table 20. The GERD population has been sub-classified into several distinct groups including a non-erosive reflux disease (NERD) group.3). about 30% experience it for over 10 years (10).Chapter 20 / Gastric Acid Secretions. Importantly.2.and under-secretion are observed in clinical practice. gastrin acts directly on the parietal cell by binding to CCK2 and induces release of cytosolic calcium which ultimately leads to the activation of the proton pump. Acetylcholine functions both by stimulating parietal cells as well as through the inhibition of somatostatin release. The main inhibitor of gastric acid secretion is somatostatin which acts to attenuate acid secretion (1. The released histamine diffuses to the parietal cells where it stimulates acid secretion via activation of histamine H2 -receptors. The active parietal cell secretes hydrochloric acid (HCl) at a concentration of 160 mM/L or pH of 0. In addition. and Nutritional Consequences 473 Gastric acid secretions are stimulated both centrally and peripherally. Central stimulation occurs via peptides that are produced in the gut and can signal the brain directly and indirectly (3). With regard to duration. 20. for acid to be secreted from the parietal cell. gastrin functions primarily by releasing histamine from ECL cells via cholecystokinin-2 (CCK2). lifelong condition that may require continuous management including symptom relief and complication management (7).2.000 people that suffer from heartburn in the US. duodenal ulcer. Lastly. a large portion of the NERD population has normal . The acid extrudes through the mucus layer based on the pressure generated during the secretion (∼17 mmHg) (1).2. hypersecretion is manifested in the Zollinger–Ellison syndrome (ZES). Treatments. 20. neural. and consequences. Individuals with HP infection also suffer from disturbances in acid secretion and interestingly colonization elicits both secretion extremes. gastric acid secretions can be modulated by infection with Helicobacter pylori (HP). The cycle is completed once the stimulus has decayed and the proton pump is internalized via endocytosis and acid secretion is terminated. the main stimulants include gastrin (hormonal). and the major symptoms are heartburn and regurgitation. In response to food.

1 Diseases Related to Perturbation in Acid Secretion Acid secretion status Hypersecretion Acid perturbation mechanism and consequences Diseasea Zollinger– Ellison syndrome (ZES) Prevalence/populations Rare condition: 1–3 cases/year/million References Chronic HP infection Hypersecretion (see hyposecretion below) 10–15% of HP cases.99) neuroendocrine tumor that causes ectopic secretion of gastrin leading to gastric acid hypersecretion • Chronic use of H2 RA and/or PPIs • Severe refractory peptic diseases and frequent complications • 60–90% of tumors are malignant (1) • Increase in the production of gastric acid perhaps due to reduced somatostatin • Duodenal ulcer mainly due to the perturbations in acid secretion (1.100. NSAIDs negative) (101) Very rare. may be related • Altered gastric Hyposecretion to other diseases mucosal defense to normal acid • Oxyntic mucosa secretion inflammation with reduced parietal mass cells Hypersecretion • Gastrinoma. antral predominant (located in the antrum – lower part of the stomach) Duodenal ulcer Gastric ulcer In children the prevalence is 1 out of 2. Improvement in Health Outcomes Table 20.474 Part V / Prevention of Major Disabilities. NSAIDs negative). In US adults it is estimated that up to 20% are idiopathic (HP negative. increased basal and stimulated acid production and/or reduced somatostatin (1) .500 hospital admissions and only about 30% was HP related (100). • Idiopathic (HP 102–104) negative. (23.

Chapter 20 / Gastric Acid Secretions. Barrett’s esophagus.106. Treatments.108) secretion is thought to facilitate survival of the organism and colonization of the stomach • Protection against GERD. prevalence and low pepsinogen increases with age (up I concentrations to 12% for 80 years • ECL cells undergo old).107) • Chronic atrophic gastritis is a precursor of intestinal gastric cancer • Initiation of the carcinogenic process in most cases related to HP infection • Decrease in acid (1. In diabetes type 1 hyperplasia which 5–10% may progress to dysplasia and gastric carcinoid tumor (4–9% of patients) • Affect the partial cells in the corpus and fundus location of the stomach • Vitamin B12 deficiency (megaloblastic pernicious anemia) • Iron deficiency anemia (in 20–40% of patients with autoimmune gastritis) (99. and Nutritional Consequences 475 Autoimmune gastritis Hyposecretion Chronic atrophic gastritis/gastric cancer Hyposecretion Acute HP infection Hyposecretion (105) General population about • High serum gastrin 2%. and esophageal adenocarcinoma (Continued) .

476 Part V / Prevention of Major Disabilities. alternatively products of the HP itself inhibit the partial cell from secreting acid Diseasea Prevalence/populations References Chronic HP infection pangastritis Hyposecretion a Other disease states that have been associated with hypersecretion such as renal failure are not reviewed here. and acid secretion • Due to the inflammation products there is a functional inhibition of the parietal cells. histamine. Improvement in Health Outcomes Table 20. .1 (Continued) Acid secretion status Acid perturbation mechanism and consequences • Nutritional consequences related to vitamin B12 malabsorption • Direct inhibition of parietal cells probably due to a constituent from the bacteria • Inhibition of expression of portion of the ATPase pump • Indirectly changing hormonal. pancreatic or neural regulatory functions • Stimulation of somatostatin thus inhibition of gastrin.

and Nutritional Consequences 477 physiological acid exposure. acid secretion. There are. gastroduodenal ulceration and is recognized as a carcinogen for its role in gastric carcinogenesis (13. the pathogenesis in GERD is mainly related to acid in the wrong place. 20. Further.2.2.2. Most gastric ulcers are thought to be due to altered gastric mucosal defense despite normal to low basal and stimulated gastric acid secretions. After the development of acid-suppression therapies especially PPIs. Bacterial and host factors contribute to the degree and severity of inflammation.2. Currently gastric ulcer is managed by inhibiting gastric acid secretion and the removal of the assaulting agent (nonsteroidal antiinflammatory drugs or management of HP infection).2. since the ulcer was not cured by the antacids recurrence and complication often resulted. HP infection is implicated with a number of extra gastric diseases (15). Infection with HP often occurs in childhood. chronic gastritis. antacids were commonly used. however. It is commonly understood that prevalence of infection is decreasing in many countries due to improvements in sanitation and living standards and the relatively recent movement of populations from rural to urban settings (12).1 describes the consequences of both hyper and hyposecretion as related to HP infection.14). Varied host immune responses to the pathogen have been documented (15). healing is correlated with duration of acid-suppressive therapy. but interestingly. However. and concomitant association with duodenal ulcer. it was possible to use these medications that allowed the duodenal ulcer to heal and further to prevent recurrence. and once established. With regard to the bacteria. Unlike duodenal and gastric ulcers where excessive acid is associated with the etiology of the disease. In contrast. surgery procedures such as vagotomy that aimed to denervate the acid-producing areas of the stomach or other more extensive ulcer surgeries such as subtotal gastric restriction were used. both nighttime and supine reflux are associated with severe esophagitis or complicated GERD. HP infection . Treatments. Increased basal and stimulated acid production is often seen with the development of duodenal ulcers. Importantly. hypergastrinemia causes acid hypersecretion in individuals with antral gastritis. Most HP-infected individuals suffer from reduced gastric acid secretion due to atrophy. U LCERS There are four types of gastric ulcers based on location. 20. Overall. adherence to gastric epithelial cells as well as the chemicals that they produce to help their survival in the acidic environment or synthesis of the cytotoxin that they produce. HP strains may differ in their motility. and longer periods of time are usually recommended. similar symptoms. Consequently. Before the invention of acid-suppressive therapies histamine H2 -receptor antagonists (H2 RAs) and proton pump inhibitors (PPIs). are experienced in both erosive and non-erosive patients. pylori (HP) is a human pathogen that has been linked with sanitation and water quality in most but not all studies (12). Notably. inactivation of the ATPase and direct inhibition of the acid secretion. and acid control is central to the management of these patients. The interaction between host genetic factors and susceptibility to HP has not been elucidated yet (16). I NFECTIONS WITH H.Chapter 20 / Gastric Acid Secretions. Eradication of HP restores somatostatin and gastrin and thus acid secretion. several complications associated with GERD that are encountered in clinical practice including reflux esophagitis and Barrett’s esophagus (9) and further. in terms of frequency and severity. HP affects half of the world’s population and is considered the major cause of acute gastritis.3. Table 20. they are more sensitive to acid than those with erosive reflux disease (11). but within a region it can vary by ethnicity and socioeconomic factors. the prevalence of HP infection is higher in developing countries when compared to developed countries. Successful eradication of the bacteria is associated with improved health outcomes including reduced peptic ulcer risk and reduced peptic ulcer recurrence (13). can persist lifelong if untreated. PYLORI (HP) H.

compounds that neutralize acid that is already in the stomach. Over 82 million prescriptions for PPIs and over 19 million prescriptions for H2 RAs are written yearly worldwide (18). patients are using PPIs on a longterm and continuous basis (19).478 Part V / Prevention of Major Disabilities. a large number of antacid compounds were recognized as safe and effective as reflected in the first over the counter (OTC) monograph that was produced by the FDA in 1974. aluminum hydroxide (Al(OH)3 ). There are numerous interventions and these are considered safe and effective.3.1. it is difficult to maintain the buffering for a prolonged period of time and repeated dosing with the antacid is needed (22). Prevalence of these diseases is summarized in Table 20. Currently. . The antacids have several important limitations. Consequently. The first was commercial in nature and required a minimum amount of each of the compounds in a formulation mixture of 25%. Currently two classes of systemic drugs are used to prevent gastric acid secretion: H2 RAs and PPIs. these combinations needed to comply with two main requirements. were used for the management of acid hypersecretion. 20. Patients with idiopathic ulcers are usually maintained on PPI therapy. in contrast. It has been reported that about two-thirds of PPI prescribing in the United Kingdom is for long-term therapy (20). Improvement in Health Outcomes is considered the root cause for most duodenal ulcers. Due to their local mode of action. however. for example. Barrett’s esophagus. sodium bicarbonate (NaHCO3 ). and magnesium hydroxide (Mg(OH)2 ) or combinations of these salts were employed throughout most of the twentieth century to manage acid hypersecretion. antacids. These medications are widely prescribed due to their beneficial therapeutic ability to reduce gastric acid secretion regardless of stimulus (1). and to prevent complications due to chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs). Antacids Antacids such as calcium carbonate (CaCO3 ). In the past. PHARMACOLOGICAL INTERVENTIONS RELATED TO EXCESS GASTRIC ACID Too much acid and especially acid in the wrong place is associated with several diseases that may require pharmacologic intervention. leading the way in acid-suppressive therapies are proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2 RAs). Additional indications also exist. PPI therapy is popular among doctors and patients and importantly. and higher doses may be required to control acid secretion and prevent ulcer relapse (17).1. Due to the large number of potential compounds used in antacid formulations. act on acid that is already in the stomach and when dosed appropriately can provide rapid and effective acid neutralization. However. For many decades antacids were the only treatment available for acid imbalance diseases.3. it is important to note that their use pattern has shifted from acute to chronic. Increased parietal cell mass due to suppression of somatostatin has been documented in HP-infected duodenal ulcer patients (1). These temporarily buffer gastric acid and provide a transient increase in stomach pH that has been associated with relief from pain. their use is limited as these do not control acid secretion and only provide temporarily relief. several PPIs are officially approved for the management of HP infection (21). 20. in Japan. mainly in the form of acid suppression. The second condition was related to efficacy and required 5 milliequivalents of acid neutralization capacity as a minimum acid neutralization capacity per dose. avoid potential complications such as the precancerous condition. It is increasingly common to take these drugs on a chronic basis to prevent recurrent gastroesophageal reflux (GERD). Antacids. strictures.

Treatments. PPIs accumulate in acidic spaces of stimulated parietal cells where their concentration can increase up to 1. The protonation of both the pyridine and the imidazole is a prerequisite for their conversion to the active drug. Several other analogues including ranitidine (Zantac). The bond between the PPI and the ATPase prevents the final stage of acid secretion. the histamine receptor and abolished gastrin but did not affect acetylcholine. omeprazole. or acetylcholine. the proton transport across the membranes from the parietal cell. gastrin. which differs across the PPI category. was introduced.3. These properties also highlight the need to consume the PPIs shortly after the initiation of a meal when the proton pump is activated (23). and perhaps to the development of tolerance as well. Consequently. It became commercially available under the brand name Tagamet. and several others . The pyridine and the imidazole are heterocyclic moieties forming the PPI prodrug that can be protonated as a function of the conditions in the acid space of the parietal cells. famotidine (Pepcid).3.5 there is greater activation. depends on the pH in the acid space and the chemical properties of the heterocyclic rings. there were several studies that documented a rebound effect (acid hypersecretion) and tachyphylaxis/tolerance with the H2 RAs after prolonged use. The activated drug forms one or more irreversible disulfide bonds with the cysteine(s) in the proton pump. At the same time this also delays the initiation of acid suppression (25). colonic epithelial cells. The PPI class is the standard drug currently used for acid-related gastrointestinal diseases. It was found later that this class of antagonist only blocked one of the parietal cell secretagogues. Uptake of PPIs by other cells such as HP. 20.Chapter 20 / Gastric Acid Secretions. the second interaction location on the ATPase differs for the different PPI drugs (dependent on the pH). the first proton pump inhibitor (PPI). and nizatidine (Axid) soon followed. Chemically PPIs are either substituted pyridylmethylsulfinyl benzimidazole or imidazopyridine derivatives. PPIs are powerful and the most effective acid secretion inhibitors due to their direct effect on the proton pump. the duration of their effects is longer than expected based on their blood levels. Importantly. Increased sensitivity or up regulation of the H2 receptor to histamine stimulation as a result of the chronic competitive inhibition is considered the main mechanism by which rebound develops. and Nutritional Consequences 479 20. the use of H2 RAs significantly reduced acid secretion but without actually totally stopping it.2. To prevent protonation in the stomach prior to duodenum absorption.000 times that of the blood. the PPI binds to the ATPase allowing for the second protonation to occur. Despite advantages that may be associated with partial acid suppression. The rate of activation. Most PPIs are taken in the form of prodrugs. The development of tolerance to H2 RAs is perceived as loss of efficacy (24). H2 -receptor antagonists work as competitive inhibitors and concerns related to rebound as a result of its mode of action surfaced soon after their introduction to the marketplace. Besides the incomplete acid suppression. Therefore. PPIs inhibit acid secretion via the attachment of their active form to the proton pump ATPase. Several other related moieties later became available. the activation of PPIs is dependent on the pH and when the pH is below 2. Following the first protonation. PPIs provide a more sustained increase in gastric pH relative to H2 RAs which only affect the histamine receptors thus allowing for some acid secretion (21). cimetidine. indicating that gastrin action was mediated via neuroendocrine cells (23). PPIs inhibit gastric acid secretion independent of gastric acid stimulators including histamine. the H2 RAs class use dramatically deceased as newer interventions that were able to totally block acid release became commercially available. all work on the same cellular mechanism.3. PPIs are formulated with an acid resistant coating. As acid is secreted by the proton pump. was developed and commercialized by Smith Kline and French in the late 1970s. Proton Pump Inhibitors (PPIs) In the late 1980s. Histamine H2 -Receptor Antagonists (H2 RAs) The first selective H2 -receptor antagonist. Hypersecretion has been demonstrated with and without a meal.

thus making this population treatment failure. However.3. These emerging therapies are considered superior alternatives to the triple therapy for treatment of patients infected with resistant strains of HP. due to increased bacterial resistance. definitive studies that demonstrate long-term success are lacking (29–32). The second line of therapy. and in certain populations in developed countries (12). Improvement in Health Outcomes has also been reported (21). 20. Further. Each line of therapy produces efficacy of about 70% (35). There is only limited information to support other interventions as first line of therapy including over the counter (OTC) antacids in combination with H2 RA or a PPI or lifestyle changes. one that emphasizes the importance of lifestyle changes to help control the triggers. and tinidazole (36). clarithromycin. Another GERD algorithm. Based on a recent meta-analysis. A third line of therapy for patients that failed both the triple and the quadruple therapy uses PPI and amoxicillin together with levofoxacin. the quadruple therapy.3. and amoxicillin or metronidazole. increasing pH to over 4 especially during the night has been recommended. S-omeprazole. it was concluded that for infrequent post-prandial symptoms antacids and antacids in combination with alginates are quite effective (33). consists of bismuth +metronidazole +tetracycline +PPI. lansoprazole. however. Fass recently reported that during a period of 7 years (1997–2004) there was a 50% increase in double dose PPI use in patients with GERD (28). these approaches are widely used in clinical practice (6). clarithromycin. clarithromycincontaining triple therapies do not reliably produce a high (at least 80%) cure rate (34). Many GERD patients that fail once a day PPI. resistance to clarithromycin and resistant strains of HP (37). The dosage forms and the indications associated with the available PPIs are tabulated in Table 20. Further. a meta-analysis of OTC medicines. and currently in development is tenatoprazole (25). Clinically available PPIs are omeprazole. is effective when resistance to metronidazole is low. pantoprazole.2. is also available (9). However. it is expected that PPIs will still prominently be recommended. Overall. the use of antacids as alginate–antacid combinations are likely to increase (9). PPIs are capable of raising intragastric pH by several units and reduce hydrogen ion concentration (acidity) by hundreds to thousands fold (26). M EDICAL T HERAPY FOR G ASTROESOPHAGEAL R EFLUX D ISEASE Medical therapy is based on the classical view of GERD and is focused on inhibition of acid production with PPIs dominating the treatment algorithm (27). An emerging alternative strategy is sequential therapy where the antibiotics are administered in sequence. and despite lack of data. and rabeprazole.3. however. there are data to support treatment with antisecretory agents. Further. are prescribed high dose of PPI but still fail to respond. For example. M EDICAL T HERAPY FOR HP I NFECTION The first-line treatment of HP infection is a triple therapy which combines PPI. The initial treatment phase includes PPI and amoxicillin followed by PPI.480 Part V / Prevention of Major Disabilities. This European algorithm focuses both on the latest clinical practice experience and is based on findings that shows that the majority of typical GERD patients have no evidence of erosive esophagitis. The recent AGA position paper concluded that empirical therapy with PPIs is appropriate initial management for patients with uncomplicated heartburn. it also highlights that despite lack of data to support PPI intervention twice a day or nocturnal dose with H2 RAs. it was concluded that in . For example. Eradication has been difficult due to both recurrence. As for lifestyle changes.3. Recurrence rates of HP infection remain high in developing countries. 20. These cells may also contain ATPases that are slightly different than the parietal cell ATPase. there are ample studies that show an association between weight and GERD.2.1. it highlights the prevalence of the documented treatment failure in this population. and that PPIs are more effective than H2 RAs.

and Elimination Routes for PPIs Indication/Dose (mg/day) and duration/recommended duration for specific indication Dosage form/Manufacturer directions Form: Delayed-release. enteric-coated tablets containing 20 mg of rabeprazole sodium Directions: Take with or without food Half-life (hours)/Elimination routes/Protein bound (%) Half-life: 1–2 h.3% (Continued) Brand Name/Chemical Name/Manufacturer Aciphex/rabeprazole sodium/Eisai (42) Healing of erosive or ulcerative GERD: 20 mg/day.2 Indications. Dosage. Remainder in feces Protein bound 96.Table 20. Elimination urine 90%. for 4–8 weeks Maintenance of healing of erosive or ulcerative GERD: 20 mg/day Treatment of symptomatic GERD: 20 mg/day for 4 weeks Healing of duodenal ulcers: 20 mg/day for up to 4 weeks .

Feces: 2/3 Protein bound 97% Brand Name/Chemical Name/Manufacturer Form: Prevacid is supplied in Prevacid/Lansoprazole Duodenal ulcer (Short-term treatment): 15 mg/day for delayed-release capsules.5 h Elimination urine: 1/3. (three times daily for 14 days) Directions: Take before Benign gastric ulcer: 30 mg/day for up to 8 weeks eating NSAIDs-associated gastric ulcer.Table 20. in /TAP (43) 4 weeks delayed-release orally Duodenal ulcer (maintenance of healed): 15 mg/day disintegrating tablets for oral HP eradication to reduce the risk of duodenal ulcer administration and in a recurrence triple therapy: 30 mg plus amoxicillin 1 g and packet for delayed-release clarithromycin 500 mg twice daily for 10 or 14 days oral suspension. risk reduction: 15 mg/day for up to 8 weeks Short-term treatment of symptomatic GERD: 15 mg/day for up to 8 weeks Short-term treatment of erosive esophagitis: 30 mg/day for up to 8 weeks Pediatric (1–11 years) short-term treatment of symptomatic GERD and short-term treatment of erosive esophagitis: 15 mg/day for up to 12 weeks for ≤30 kg. Each form HP eradication to reduce the risk of duodenal ulcer is available in either 15 or recurrence dual therapy: 30 mg plus amoxicillin 1 g 30 mg strengths. healing: 30 mg/day for 8 weeks NSAIDs-associated gastric ulcer. 30 mg/day for up to 12 k for 30 kg Adolescent (12–17 years) Short-term treatment of symptomatic GERD Non-erosive GERD: 15 mg/day for up to 8 weeks Erosive Esophagitis: 30 mg/day for up to 8 weeks Maintenance of healing of erosive esophagitis: 15 mg/day Pathological hypersecretory conditions including ZES: 60 mg/day .2 (Continued) Indication/Dose (mg/day) and duration/recommended duration for specific indication Dosage form/Manufacturer directions Half-life (hours)/Elimination routes/Protein bound (%) Half-life: 1.

Clarithromycin 500 mg (three times daily for 14 days) Gastric ulcer: 40 mg once daily for 4 to 8 weeks GERD: 20 mg once daily for 4–8 weeks Maintenance of healing of erosive esophagitis: 20 mg once daily Pathological hypersecretory conditions: 60 mg (varies with individual patient) once daily Pediatric patients (1–16 years of age) Form: Prilosec delayed-release capsules: 10 mg. Each drug twice daily for 10 days Dual therapy: PRILOSEC 40 mg (once daily for 14 days). stirred. Packets for delayed-release oral suspension should be emptied into a container containing water (5 mL water for a 2. Some patients may require an additional 4 weeks HP eradication to reduce the risk of duodenal ulcer recurrence: Triple therapy: Prilosec 20 mg. 20 mg. Remainder in feces Protein bound: 95% GERD and 5–10 kg maintenance of 10–20 kg healing of erosive ≥20 kg esophagitis (Continued) . Amoxicillin 1. and Clarithromycin 500 mg.Prilosec/Omeprazole (delayed-release capsules) Omeprazole magnesium (for delayed-release oral suspension)/ AstraZeneca (109) Short-term treatment of active duodenal ulcer: 20 mg once daily for 4 weeks. and stirred and drank within 30 min. add more water. stir and drink immediately.5–1 h Elimination urine: 77%. and 40 mg Prilosec for delayed-release oral suspension: 2.5 mg packet and 15 mL of water for a 10 mg packet).5 or 10 mg Directions: Delayed-release capsules should be taken before eating and swallowed whole.000 mg. If any material remains after drinking. Once daily Weight 5 mg 10 mg 20 mg Dose Half-life: 0. allowed to thicken for 2–3 min.

2 (Continued) Indication/Dose (mg/day) and duration/recommended duration for specific indication Form: Delayed-release tablet available in two strengths. Remainder in feces Protein bound: 97% .000 mg twice daily for 10 days and clarithromycin 500 mg twice daily for 10 days Adolescent Use 12. For delayed-release oral suspension contains 20 or 40 mg of esomeprazole.5 h 20 mg dose: 1. in the form of the same enteric-coated granules used in Nexium delayed-release capsules. Doses as high as 240 mg/day have been administered GERD. maintenance of healing of erosive esophagitis: 20 mg/day Symptomatic GERD: 20 mg/day for 4 weeks Risk reduction of NSAIDs-associated gastric ulcer: 20 or 40 mg/day for up to 6 months HP eradication to reduce the risk of duodenal ulcer recurrence. Each packet of Nexium. Directions: At least 1 h before meals Dosage form/Manufacturer directions Half-life (hours)/Elimination routes/Protein bound (%) Half-life: 1 h Elimination urine: 71%.to 17-year olds. Each delayed-release tablet contains 45. respectively) Directions: Take with or without food Form: Nexium is supplied in delayed-release capsules and in packets for a delayed-release oral suspension. short-term treatment of GERD: 20 or 40 mg/day for up to 8 wk Pathological hypersecretory conditions including ZES: 40 mg twice daily Half-life: 40 mg dose: 1. triple therapy: 40 mg/day for 10 d plus amoxicillin 1.1 or 22.2 h Elimination urine: 80%. Each delayed-release capsule contains 20 or 40 mg of esomeprazole. Feces: 18% Protein bound: 98% Brand Name/Chemical Name/Manufacturer Protonix/Pantoprazole sodium/Wyeth (110) Nexium/esomeprazole magnesium/ AstraZeneca LP (44) Treatment of erosive esophagitis: 40 mg/day for up to 8 weeks Maintenance of healing of erosive esophagitis : 40 mg/day Pathological hypersecretory conditions including ZES: 40 mg twice daily for as long as clinically indicated. healing of erosive esophagitis: 20 or 40 mg/day for up to 4–8 weeks GERD.6 mg of pantoprazole sodium sesquihydrate (equivalent to 40 or 20 mg pantoprazole.Table 20.

Packets of powder for oral suspension contain either 40 or 20 mg of omeprazole and 1.680 mg of sodium bicarbonate.Zegerid/Omeprazole sodium bicarbonate/ Santarus (45) Short-term treatment of active duodenal ulcer: 20 mg/day for 4 weeks Benign gastric ulcer: 40 mg/day for 4–8 weeks Symptomatic GERD (with no esophageal erosions): 20 mg/day for up to 4 weeks GERD with erosive esophagitis: 20 mg/day for up to 4–8 weeks Maintenance healing of erosive esophagitis: 20 mg/day Reduction of risk of upper gastrointestinal bleeding in critically ill patients : 40 mg initially followed by 40 mg 6–8 h later and 40 mg/day thereafter for 14 days (oral suspension only) Form: Immediate-release capsules and unit-dose packets as powder for oral suspension. Directions: On an empty stomach at least 1 h before a meal Half-life: 1 h Elimination urine: 77%.100 mg of sodium bicarbonate. Remainder in feces Protein bound: 95% GERD—gastroesophageal reflux disease. NSAID–nonsteroidal anti-inflammatory drugs. . pylori. ZES—Zollinger–Ellison Syndrome. Each capsule contains either 40 or 20 mg of omeprazole and 1. HP–H.

. that has a buffering capacity because it has been shown that absorption of Prevacid and omeprazole is delayed and bioavailability reduced when administered with sucralfate (43). It is well known that the use of NSAIDs is associated with upper GI complications such as GI bleeding. PPIs should not be co-administered with atazanavir. Prevacid. The combination of PPI with COX-2 has been shown to enhance the gastroprotective efficacy relative to COX-2 alone. concomitantly may experience increased risk of bleeding due to increases in the international normalized ratio (INR) of platelets and increase in prothrombin time (42–45). at times. readjustment of the PPI and/or the co-administered drug may be required. Notably.3. 20. clarithromycin. Gastroprotective therapies include cyclooxygenase-2 (COX-2) inhibitors. and new strategies including vitamin C in combination of aspirin (40).486 Part V / Prevention of Major Disabilities. amoxicillin. Similarly. To overcome the complications of NSAIDs. it was reported that H2 RAs did not reduce the gastrointestinal complication risk while on NSAIDs (39). and symptomatic peptic ulcer disease. PPIs are considered as primary gastroprotective agents in gastrointestinal complications in cases of NSAIDs. which depends on an acidic gastric pH for absorption (43–45). For example.3. or cotherapy with PPIs or misoprostol.4. M EDICAL T HERAPY FOR G ASTROESOPHAGEAL C OMPLICATION I NDUCED BY N ONSTEROIDAL A NTI . dose adjustment upward may be required in patients with Zollinger–Ellison’s Syndrome (ZES) (44). and Zegerid decrease plasma levels of the human immunodeficiency virus (HIV) protease inhibitor atazanavir. an older medication for the treatment of GERD and active duodenal ulcers. PPIs may also interfere with the bioavailability of drugs that are dependent on gastric pH. non-users in contrast are at a lower risk for developing such complications (39). Improvement in Health Outcomes developing countries recurrence is related to infection with a new strain while in developed countries it is due to re-infection with the same strain (38). and their use significantly increased with the withdrawal of COX-2 (41). These upper GI complications develop in about 1–2% of NSAIDs users. such as voriconazole.INFLAMMATORY D RUGS (NSAID S ) Both prescription and OTC nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for relief of pain and inflammation associated with musculoskeletal injury and arthritis. PPIs should be taken 30 min prior to sucralfate. several gastroprotective strategies including certain drugs and drug combinations have been used. In contrast. Prevacid. and clarithromycin (42). ulcer perforation. This is especially important as the standard treatment for HP infection may include the combination of these drugs.3. In addition. 20. Increases in plasma concentrations of both PPI and antibiotic drugs have been observed when these are taken concomitantly. commonly used gastroprotective strategies reduce the risk of upper GI complications in NSAIDs users. For example. Drug–Drug Interactions There are certain drugs that are affected by co-administration with PPIs and. increased plasma concentrations of rabeprazole and 14-hydroxyclarithromycin may be experienced by individuals administered combinations of rabeprazole (Aciphex). Although not normally required. Doubling of esomeprazole activity level may result from concomitant administration of esomeprazole (Nexium) and a combined inhibitor of certain cytochromes including CYP2C19 and CY3A4. and Zegerid). Notably. and 14-hydroxyclarithromycin may occur when omeprazole (in the drug Zegerid) and clarithromycin are co-administered (45). increases in plasma levels of omeprazole. Nexium. PPIs and drugs that are metabolized by cytochromes in the liver including certain cytochromes (CYP2C19) may be affected due to co-administration.3. Nexium. Patients receiving warfarin and PPIs (including Aciphex.

Prevalence ranging from 3 to 40% was reported (49). and therefore reduced gastric acid may result in reduced B12 bioavailability. the intake of other PPIs like pantoprazole or esomeprazole was not associated with impaired response to clopidogrel (47). Vitamin B12 (cobalamin) deficiency is prevalent in the elderly with potential irreversible hematological and neurological consequences affecting sensory and motor function if unrecognized and untreated. and phenytoin. There are only a few studies where reduced vitamin B12 status was clearly demonstrated.Chapter 20 / Gastric Acid Secretions. The consequences of reduced vitamin B12 absorption may take years to develop because the body is able to reutilize vitamin B12 by enterohepatic recirculation. and Nutritional Consequences 487 Zegerid may prolong the elimination of drugs that are metabolized by oxidation in the liver. and importantly that about half of those affected are clinically symptomatic (50. 20. and dairy products where it is bound to protein. fish.4. Zegerid may increase serum levels of tacrolimus (45). More subtle effects have also been described. Treatments. 20. Other markers of vitamin B12 deficiency such as homocysteine and methylmalonic acid levels could be used to demonstrate earlier deficiency manifestation. eggs. This study identified .4%) after doubling the omeprazole dose (53). The majority of dietary vitamin B12 is found in meat. therefore allowing for earlier diagnosis and thus enable corrective actions before complications develop (49).9%). Vitamin B12 and Gastric Acid Acid and pepsin are needed for the digestion of protein and the release of the vitamin B12 from dietary sources where vitamin B12 is usually protein bound. mixed data have been reported in relation to the usage of acidsuppressive therapies and vitamin B12 status. including diazepam. Most cases of vitamin B12 deficiency may be due to either reduced intake or malabsorption.6 to 0. and most patients will not manifest signs and symptoms of vitamin B12 deficiency until at least 3 years of no vitamin B12 absorption (51). Additional data to support the association between acid-suppressive therapies and vitamin B12 status come from a retrospective case–control state-wide Medicaid drug database. neurocognitive impairment. A dose–response reduction in vitamin B12 absorption has been demonstrated in healthy individuals that were treated with omeprazole for 2 weeks. It was hypothesized that omeprazole competes with liver enzymes that metabolize clopidogrel (Plavix) resulting in enhanced platelet activity (reduced efficacy of the clopidogrel) for patients who are taking the anti-platelet drug.1. Populations at risk for vitamin B12 deficiency include strict vegetarians as vitamin B12 is found primarily in animal-based foods. poultry. and a further reduction in vitamin B12 absorption was observed (from 3. Some but not all studies showed a reduced vitamin B12 status with increased duration of acidsuppressive therapy. and increased vascular disease risk associated with elevated homocysteine (48). Reduced intake may be due to lifestyle choices and may be related to economic status (52).2 to 0. NUTRITIONAL CONSEQUENCES OF REDUCED GASTRIC ACID Long-term decrease in gastric acid has been associated with several effects on nutritional status. Also.51). However. Absorption of vitamin B12 was reduced about fourfold after ingestion of 20 mg omeprazole (from 3. Recently there is some evidence that suggests that omeprazole may negatively affect cardiovascular events in patients who also take clopidogrel. tacrolimus (a macrolide). In contrast to the reported negative omeprazole–clopidogrel drug interaction.4. Gastric acid is central to the release of vitamin B12 . clopidogrel (46). Others suggest that between 10 and 20% of the population is affected. when administered concomitantly with the immunosuppressive drug. including osteopenia. it appears that this is not a class effect. Despite strong biological plausibility. Several studies ascertained the relationship between acid-suppressive therapies and vitamin B12 status. warfarin.

there are epidemiological. In addition to the many well-established roles of vitamin C. and a reduced antioxidant potential. compared to 11% of the control group who initiated vitamin B12 therapy. Importantly. Ascorbic acid is present in small concentration in human saliva and it is actively secreted into the gastric lumen. and those who chronically use acid-suppressive therapy may be affected. Diminished serum vitamin B12 was demonstrated based on a study of 542 elderly patients who were PPI users but not those who used H2 RAs. The odds ratio for the initiation of vitamin B12 therapy was significantly higher for users of acid suppressives. and the average duration was 18 months. ascorbic acid is rapidly oxidized even under fasting conditions.2. as expected. Reduced vitamin C levels both in plasma and in the affected tissues of individuals who suffer from esophageal adenocarcinoma relative to matched healthy individuals suggest a role for oxidative stress in the pathogenesis and progression of esophageal adenocarcinoma (see Chapter 6) (56). Improvement in Health Outcomes 125 patients who started vitamin B12 supplementation (via injection) during the study period as cases and 500 matched controls. however (55). long-term study of PPI use and vitamin B12 status showed a significant trend toward reduced vitamin B12 levels with increased duration of PPI therapy. The results from randomized trials are not consistent. 20. This compromised capability may manifest itself in diseases such as iron deficiency and iron deficiency anemia as well . Its primary evolutionary benefits may stem from its functions related to nitrite and iron chemistry (26).4. evidence of vitamin B12 appears only after many years on PPI therapy. Vitamin B12 therapy reduced vitamin B12 deficiency markers and confirmed the effect of PPI (54). despite different etiologies in the development of gastric relative to esophageal cancers. those who have atrophic gastritis. while 18% of the users of acid-suppressive drugs initiated vitamin B12 therapy. antioxidants may also protect against the development of esophageal adenocarcinoma. 40 mg dose of omeprazole (PPI) significantly reduced fasting gastric levels of vitamin C. absorb iron.488 Part V / Prevention of Major Disabilities. a drop of 46% over 12 years. experimental. concomitant oral B12 supplementation slowed but did not prevent the decline in vitamin B12 status seen when longterm PPI therapy was used. a recent small. and that the effect on the active form. those who are infected with HP. Ascorbic acid is thought to have a critical role in the management of toxic nitrogen species (57). Achlorhydric patients (gastric restriction or vagotomy). Patients with gastrinoma (ZES) and without gastrinoma that were acid hypersecretors and were treated with lansoprazole (PPI) with an average treatment of 140 months were studied. Therefore. Importantly. It is plentiful in fruits and vegetables. In addition. and animal data that indicate that diets that are high in fruits and vegetables (a source of vitamins and minerals) may reduce the risk of gastric cancer. individuals that are on omeprazole therapy have a limited capability to reduce nitrite levels. It was concluded that patients initiating vitamin B12 therapy were more likely to be receiving long-term acidsuppressive therapy (51). ascorbic acid was even more profound. Other populations at risk for vitamin B12 deficiency include patients that suffer from acid imbalance. Overall vitamin B12 went down from a median between 890 and 950 pg/mL in the first few years to 495 pg/mL. Vitamin C and Gastric Acid Vitamin C (ascorbic acid) is a water soluble antioxidant and a reducer of carcinogenic nitrite. In the upper part of the stomach. Twenty eight percent were using H2 RAs only and 26% were using PPI only. Finally. therefore limiting its antioxidant capability. McColl’s team demonstrated that in healthy volunteers. Ten percent had low serum vitamin B12 and 31% had normal vitamin B12 but had other symptoms related to vitamin B12 deficiency. The vitamin B12 status of the 141 PPI users was evaluated as a function of time and further the effect of duration of use of PPI was evaluated with and without vitamin B12 supplementation. Chronic acid-suppressive therapy was defined as either H2 RAs or PPI use for 10 of the 12 previous months.

ionic radius. Calcium has many critical biological roles and is necessary to sustain life. Calcium and Gastric Acid Calcium is the most common mineral in the human body and 99% of the body’s total calcium is present in the skeleton and teeth.59). These results indicate that the effect of omeprazole therapy is further complicated by HP status (59. pH may affect both active and passive calcium transport.3. Calcium (Ca+2 ) is absorbed in the intestine via two mechanisms: an active. in the presence of a meal. calcium is transferred across membranes into the extracellular space. While on omeprazole and regardless of the HP status. First. 25 dihydroxy vitamin D and calcium concentration (63) as well as the concentration of “free” calcium. One way in which acid-suppression therapy may affect calcium absorption is based on the reduced stomach acidity. it has been difficult to demonstrate such an effect. Bo-Linn and colleagues demonstrated that calcium solubility was not a prerequisite for absorbability (66). Interestingly. The amount of calcium absorbed is dependent on the bioavailability of the calcium in the diet and the capacity for absorption in the intestine (which is regulated at least in part by 1. and interestingly. the bones. In terms of the active transport the pore structure that is associated with the process may be affected due to the change in the confirmation of the proteins and in particular it is suspected that the ionic amino acids like glutamate act as a “pH sensor. and calcium carbonate. it has been suggested that pH affects the tight junctions that control the passive absorption from the lumen into the interstitial spaces (64). there was a reduction in the active form of vitamin C. The second absorption mechanism is a passive. calcium deficiency does not manifest itself as shortage of calcium for cellular or physiological processes rather as a decrease in the calcium reservoir itself. 25 dihydroxy vitamin D). classical epithelial transcellular transport occurs with the help of the calcium-binding protein calbindin and calcium ATPase pump. ascorbic acid. Calcium absorption has been shown to be greatly enhanced by consumption with a meal. Reduced serum concentration of vitamin C was also noted as a function of HP status (58. paracellular absorption. The active. due to complex and confounding effects such as source of calcium and co-ingestion with food. The amount of calcium transferred is dependent on the lumen’s permeability which is influenced by 1. Calcium is the most studied mineral in relationship to human health (see Chapter 19) (62).4. was reduced only in the HP positive subgroup. Further. 20. Treatments. In vitro calcium solubility is dependent on pH. showed that when solubility increased by a factor of over 100. however. calcium citrate. ingestion of food is usually followed by a 2–3 units . transcellular and a passive. Stomach pH may affect the intestinal calcium absorption in several ways. The majority of ingested calcium is not absorbed and it is excreted in the feces.” Similarly. In this process. Total vitamin C.Chapter 20 / Gastric Acid Secretions. This process occurs through the length of the intestine. absorbability only doubled. (67). bioequivalent calcium absorption from calcium salts that are opposite in their neutral pH solubility. also demonstrated that calcium solubility was not a prerequisite for efficient absorption (68). the solubility of the calcium salts is dependent on their physical and chemical properties and in particular solubility is a function of pH. however. The long-term effects of acid-suppressive therapy. and in particular that of PPIs due to their more effective acid suppression. paracellular process that allows calcium to permeate across gap junctions. Active transport occurs primarily in the duodenum and upper jejunum (closer to the stomach). In addition. on bone homeostasis have not been extensively studied (65). there are data that demonstrated that in vitro solubility does not truly represent human physiology as it relates to calcium absorption. Calcium’s functions stem directly from its chemical properties including intermediate binding affinity. and Heaney et al.60). and coordination number which together allow flexibility in its interactions (61). however. and Nutritional Consequences 489 as negative gastric outcomes as discussed above.

5% (on omeprazole). Interestingly.45. however. Subjects were sampled from the Danish population and eligible cases consisted of 124. one with achlorhydric individuals (Recker (70)) and one with healthy volunteers on omeprazole (40 mg/day) (Serfaty-Lacrosniere (71)). Increased risk for hip factures was first reported for the H2 RA cimetidine in a small case–control study with 356 men with a radiologically confirmed hip fracture and 402 controls. In the placebo. the role of food and that of gastric acid (or pH) in calcium absorption appears to be conflicted and inconclusive. an effect that holds even for small meals such as breakfast (69). The results indicate that after ingestion of the test meal. Significant increased risk with an odds ratio of 2.962 were matched by gender and age from the same database. calcium was provided as isotope-labeled calcium carbonate. PPIs significantly increased the risk of fractures (OR 1. 20 mg every 8 h) on calcium absorption and urinary calcium excretion. calcium from calcium carbonate was absorbed to a much smaller degree in achlorhydric (0.2. Notably. G ASTRIC ACID S UPPRESSION AND F RACTURES : E PIDEMIOLOGICAL S TUDIES While calcium absorption studies provide conflicting data. Despite stimulation of acid secretion due to consumption of a meal. while H2 RAs reduced the risk of any fracture (OR 0. Improvement in Health Outcomes increase in the stomach pH (from about 1 or 2 to well over 4). hip and spine fractures).88) and hip fractures (OR 0.225). without a meal. directional consistency was revealed based on one earlier small and three recent large epidemiological studies (74–77).490 Part V / Prevention of Major Disabilities. there were two studies where calcium absorption was affected by the use of acid-suppressive therapy.4. 20. the food’s large buffering capacity results in a net increase in pH. Vestergaard et al.1 (on placebo) to 3. however. Exposure and variable confounders included antacids and acid-suppressive therapies and several other drugs that may interfere with calcium absorption or resorption.047) compared to normal individuals (0.1. Finally. The control group of 373. urine calcium level was higher than after omeprazole where calcium excretion over a 24 h period was 33% lower (73).3. The Serfaty-Lacrosniere (71) study demonstrated that omeprazole did not negatively affect calcium absorption when the calcium was part of a meal (milk and cheese). These studies demonstrate the effect of acid-suppressive therapy on increased risk of fracture. at 500 mg of elemental calcium without a meal.60 for overall. G ASTRIC ACID AND C ALCIUM A BSORPTION The effect of achlorhydria or acid-suppressive therapy on calcium absorption was evaluated in several studies.18. Notably. Of importance in this study. For calcium citrate. One thousand mg of elemental calcium were provided in the form of food (milk and cheese) in a single meal. 20.69). and 1.453 for the achlorhydric. Omeprazole significantly impaired calcium absorption. Calcium balance was also affected as was seen by urinary calcium excretion. but did not change when volunteers were taking omeprazole. there was no difference in calcium absorption. calcium absorption was reduced from 9.243 for the normal individuals and doubled to 0. calcium plasma level increased in the placebo. showed that when calcium was taken with a meal. in a small placebo-controlled study with eight healthy male volunteers. 1.655 individuals who suffered a fracture in the calendar year 2000. (75) in a case–control study were the first to demonstrate that PPI use was associated with increased risk of fractures. in fact. Graziani and colleagues evaluated the effect of a high dose of omeprazole (60 mg/day. O’Connell (72) evaluated the effect of 20 mg of omeprazole on calcium absorption in a placebo-controlled study. This early finding was followed by several large epidemiological studies showing similar effects. due to the method by . In contrast to these two studies where reduced stomach acidity did not seem to affect calcium absorption.3.4. Therefore. The Recker (70) study.5 was reported (77). Two small studies. showed the importance of the meal when calcium was provided as calcium carbonate or calcium citrate. calcium absorption was not dependent on co-ingestion with a meal and the fraction absorbed was found to be 0.

respectively. (79) also demonstrated increased risk of vertebral fractures in postmenopausal women recruited from five European centers.346 for nonvertebral fracture analysis.3. and importantly. In the men’s cohort there was a 50% increase in PPI use during the study (average 4.58 for 1–4 years.44 for more than 1 year of PPI therapy. Overall. Roux et al. Exposure to PPIs for over 7 years was associated with increased overall fracture risk. While PPIs primarily act on the gastric parietal cell ATPase.55 after 7 years of PPI use. Treatments. Yu et al. and perhaps older men with low calcium intake. may be associated with a modestly increased risk of nonspine fractures. sex. In the multivariate analysis. Canada. vertebral. There was also an association of a slight increased risk of nonspine fracture among men who were not taking calcium supplements. estimated that one extra nonspine fracture would be expected for every 10 women treated with PPIs for 5 years and concluded that the use of PPIs in older women.6 for hip fracture after 5 years increased to 4. it was independent of age (78). After multivariate analysis. a lower cross-sectional bone mineral density (BMD) was observed for men. and Nutritional Consequences 491 which the data were collected the population was not restricted by age (75). While studying the effects of long-term PPI use. OR of 1. omeprazole was a significant and independent predictor of fractures with a relative risk of 3.386 controls in the United Kingdom.1 years for the Osteoporosis and Ultrasound Study. when the combination of therapies (either PPI or H2 RAs) was examined. and that about 50% of the women and 35% of the men were taking calcium supplements. Adjusted odds ratio (AOR) was 1. In terms of fracture outcomes. one of 5. 20.339 women over the age of 65 (18). the PPIs exert their activity via their attachment to the ATPase and prevention of acid secretion.792 fracture cases and 47.211 women were used for vertebral fracture and 1. Total bone loss at the hip was also only significant in men who used PPI or H2 RAs. In the second prospective study.6 years. The first prospective study examined the association between acid-suppressive therapy and skeletal outcomes using two large cohorts. there were 15. mean duration of PPI therapy was 1. data from 1.755 men and the other of 5. there were no significant BMD differences among women. Similarly when comparing duration of PPI therapy. There were a total of 822 men and 753 women that were either PPI or H2 RA users.9 years).Chapter 20 / Gastric Acid Secretions.65 for longer term and higher dose. It is important to note that in the women’s cohort.3.8 years and that of H2 RAs was 3. and other comorbidities and AOR was calculated.1. Yang et al.289 controls and follow-up for over 5 years for about a 1/3 of the cohort. G ASTRIC ACID S UPPRESSION AND F RACTURES : P ROSPECTIVE S TUDIES There are now two prospective studies that also support the other epidemiological findings. and wrist fractures who were over 50 years old were matched with three controls based on age. About 2. It has been suggested that one way to explain the mechanism by which the PPIs increase the risk of fractures is related to their activity on the osteoclast ATPase. AOR increased from 1.400 women were recruited from 1999 to 2001 and were followed for a mean 6. and interestingly. up to 2. Radiographs were preformed in the beginning and in final visit and omeprazole exposure and potential cofounders were also ascertained.6 years). there was a threefold increase in the number who used PPI therapy during the duration of the study (average 4.556 cases of hip fracture and 135.22 to 1.4. Similar observations were also reported based on a very large nested case–control study with 13. As described above. PPIs can also exert some activity on the bone’s osteoclast ATPase . The relationship between duration of exposure to PPIs and osteoporosis-related fractures was also explored by Targownik (76). In a retrospective cohort based on medical claims data in Manitoba. there was a 34% significant increased risk of nonspine fracture in the women PPI users and a 20% increase when looking at PPI or H2 RAs users. showed that both men and women PPI users over 50 years old were at increased risk of hip fracture and that the risk increased with increased duration and dose of PPI (74). patients with hip. Baseline characteristics revealed that dietary elemental calcium intake was slightly over 700 mg.

In summary. Ascorbic acid in the stomach enhances absorption of nonheme iron. whereas most of the nonheme iron is in the ferric (Fe+3 ) form. or the small number of people who were actually on acid-suppressive therapies. achlorhydria has been associated with increased risk of iron deficiency and is seen most frequently in the elderly (84–86). reduced iron absorption is advantageous. Further. most studies consistently show an association of low magnitude between long-term PPI use and increased risk of all fractures and/or hip fractures.492 Part V / Prevention of Major Disabilities.82). The level of gastric acid in the stomach also affects the potential to absorb iron. such as citric.2 g of magnesium hydroxide and 90 mg simethicone) also reduced iron absorption by 52% (85). The heme iron is in the ferrous form (Fe+2 ).4. 20. and the ferric form requires reduction (in the presence of acid) to the ferrous form before it can be transported across the intestinal lumen and absorbed (80). There is a separate transporter protein for nonheme iron. iron absorption was reduced by 42 and 65% with the increase in cimetidine to 600 and 900 mg. Iron Absorption and Gastric Acid Iron absorption is highly regulated and is primarily dependent on the level of iron stores and erythropoietic activity. Improvement in Health Outcomes activity.1. In contrast nonheme iron absorption is dependent on its solubility and interactions with other meal components. Heme iron is relatively more bioavailable and is only slightly influenced by dietary factors. In contrast. lactic. increases the risk of fractures. the prospective study did not provide enough data to support reduced BMD as a cause for the fracture findings. While iron absorption was reduced by 28% when 300 mg of cimetidine was administered.4. Currently. Localization of the PPIs activity may be related to the general structure as well as the different sub units of the ATPase in the parietal cell and osteoclast in bone (78). Although these studies may not be as conclusive as placebo-controlled intervention studies. Recent data indicate that long-term use of PPIs in patients with HH reduced the requirement for maintenance phlebotomy.4. respectively. in patients with abnormally high absorption of iron (hereditary hemochromatosis (HH)). and in particular PPIs consistently albeit to a small degree.4. Gastric acid is needed to maintain nonheme iron in solution in the ferrous form and therefore decreased stomach acid may lead to impaired iron absorption (81. increased PPI dose and/or duration also consistently contributed to the increased risk. As summarized by Richards and Goltzman (79). and malic acid also enhance nonheme iron absorption. antacid (1. clinicians should help patients understand risk-benefit and especially after long-term use. 20. G ASTRIC ACID S UPPRESSION AND I RON A BSORPTION A small study using radioactively labeled iron (nonheme) and cimetidine (H2 RA) showed a reduction in the percent of iron absorbed that was dose dependent.2 g aluminum hydroxide and 1. Other organic acids. the totality of the data begins to indicate that the use of acid-suppressive therapy. primarily through reduction of ferric iron to the ferrous form (83). It was concluded that administration of a PPI to patients with HH can inhibit the absorption of nonheme iron from a test meal and the habitual diet (87). heme and nonheme. Overall. Iron in the diet can be divided into two forms. . they illustrate that more research is needed into the effects of long-term use of PPIs. Similarly. PPI-induced suppression of gastric acid reduced dietary iron absorption in the patients and there was a significant reduction in the volume of blood needed to be removed annually while on the PPI. There may be situations where reduced dose and/or finite duration should be considered (79). perhaps due to the relatively short duration.

Nutritional Consequences Summary Increasing evidence suggests that acid-suppressive therapies. In the case of pathogenic assault. Gastric acid is one of the protective agents available to help protect against microbial pathogens reaching the intestine (88). Infectious Diseases Several lines of defense mechanisms exist to protect the internal environment from potential toxins and microbial pathogens. there are local GI factors that are mobilized and.4.4.642 cases based on well-defined hospital discharge diagnosis with 34. Further there was no association with H2 receptor antagonists or with past use of PPIs (90). Children who were referred to centers with common GERDrelated symptoms and received either ranitidine (H2 receptor antagonist) or omeprazole (PPI) and others that visited the center for routine examinations were included in the study. The incidence of community-acquired pneumonia prior to the study was similar across the groups. However. C OMMUNITY-ACQUIRED P NEUMONIA C ASE –C ONTROL AND P ROSPECTIVE S TUDIES Gulmez et al. in addition if needed.176 control subjects matched by age and sex. It was reported that the adjusted odds ratio of the association between current use of PPI with community-acquired pneumonia was moderate. and Nutritional Consequences 493 20.6. except for GERD. 12% of those on the acid-suppression therapy suffered from pneumonia (91). at 1. Finally.6. the association was not PPI dose dependent. . lifestyle influences. Logistic regression was used to control confounders. Despite these limitations it is important to note that these adverse events have occurred and that risk-benefit analysis should always consider the potential for adverse nutritional effects. these children were healthy and had no co-morbidities. and other OTC medication intake.1. no conclusive data are available based on short-term intervention studies that evaluate the effect of acid-suppressive therapies on calcium absorption. Data were from 186 subjects of which 95 were in the control group and 91 received acid-suppression therapy (47 on ranitidine and 44 on omeprazole). Structural integrity combined with protective agents help to maintain the gastrointestinal tract. in the cases of vitamin B12 and iron much smaller cohorts have been used to demonstrate the effect. In some cases. such as in the increased risk of fractures. systemic immune responses are available to help prevent the pathogenic invasion. Importantly. (90) reported increased risk of community-acquired pneumonia in PPI users in a population-based study in Denmark. The study found that 2% of the control children suffered from pneumonia in the follow-up period. Further. While these observational studies use large databases that carefully document both the cases based on disease codes and medication usages. Consequences include reduced mineral and vitamin absorption. the association between acid-suppressive therapies and adverse events is based primarily on observational studies (74–76). 20.Chapter 20 / Gastric Acid Secretions.5. A prospective study with children also demonstrated increased risk for community-acquired pneumonia in children who were on gastric acid-suppression therapy.5. There were 7. are not without risk. and in particular long-term PPI use. Treatments. it is important to note that such associations are prone to confounders such as other conditions. Data are currently accumulating with regard to increased risk for both upper and lower GI tract infections. and statistically significant.4. gastric content is capable of killing bacteria within 15 min (89). The potential for increased susceptibility to infections as a complication of acidsuppressive therapy and in particular PPIs has been suggested in the past based on reduced stomach acid or hypochlorhydria. At a low pH (below pH 3). 20.

however. There were 1.2. the vegetative stage is acid sensitive so overall the impact of decrease in gastric acid is biologically plausible (93). when used chronically. Again in this population there was no association of C. Most. In another case–control study (97).4. are associated with negative nutritional and other negative consequences.672 cases of C.187 inpatients in a Montreal teaching hospital who received antibiotics in the previous 9 months and who also received acid-suppression therapy were compared to those that did not receive acid-suppression therapy. difficile often follows (92). there were 94 cases of positive C. Despite the plausible connection between the role of gastric acid in preventing C. Treatment failures. there are data indicating that these interventions especially PPIs. difficile with the use of acid suppression. despite being asymptomatic. difficile infection is prior use of antibiotics. difficileassociated disease (CDAD) are related to the kind and amount of toxins that the C. In a retrospective case– control study in the United Kingdom. Controls were selected and matched from the hospital population (93). it was not possible to ascertain the reason for the prescription of the acid suppressers. The most common risk factor for C. studies indicate increased risk for C.5. The adjusted odds ratio was 2. after the loss of commensal bowel flora opportunistic colonization with C. The clinical results of C. 20. In a 2004 article (96). it was demonstrated that recent use of PPIs was associated with a 2. Only 32% of the patients in the control group were PPI users (92). Importantly. difficile and PPIs use was significant at 2. C. the use of PPIs was associated with increased risk of CDAD. difficile and 94 controls. The cases included 176 inpatients that were positive for C. (97) confirmed previous results in a population-based case–control study with a United Kingdom population based on the General Practice Database. Again the users of PPIs had a higher odds ratio of 2. difficile and 10 matching controls were selected for each case. there was no increased risk with the use of H2 RAs.7 for the development of C. All subjects that had CDAD infection used antibiotics several months prior to the onset of the CDAD (from 2 to 5 months) and 60% were on PPIs. This was a 347 bed long-term care facility and there were 25 cases of CDAD during the study period and 28 other patients were selected as control. about 50% of the patients receiving antibiotics were also prescribed PPIs and another 10% receiving H2 RAs.1. Further. our increasing knowledge related to the . 1. the disease may not occur unless the normal flora is disturbed. difficile colonization. difficile. difficile infection (97). Dial and colleagues reported several studies all indicating increased risk of CDAD with use of acidsuppression medicines (95–97). In a US study carried out in a nursing home setting. difficile. Loss of normal gastric acidity has been associated with colonization of the gastric and duodenal portion of the upper gastrointestinal tract (94). difficile illness while on H2 RAs (96).494 Part V / Prevention of Major Disabilities. Although the spores are resistant to acid. conducted in a separate Montreal teaching hospital.5 odds ratio increased risk of C. however. Interestingly. and further. difficile in considered the main cause of colitis and is associated with increased mortality and morbidity and increased length of stay. illustrate that not all gastroesophageal diseases are caused by hypersecretion. therefore of economic significance (93).6. It has been suggested recently that acid-suppression therapy is overused in hospitals and that many patients continue to take the medication even 3 months after discharge (98). The odds ratio for the association between C. CLOSTRIDIUM DIFFICILE-A SSOCIATED D ISEASE AND G ASTRIC S UPPRESSION Clostridium difficile is a gram-positive anaerobic spore-forming bacterium that is strongly associated with hospital-acquired diarrhea in developing countries. but not all. In the hospital setting. CONCLUSIONS Acid-suppressive therapies and in particular PPIs have transformed our ability to regulate gastric acid secretion and overcome diseases associated with hypersecretion. In 2005 Dial et al. difficile produces.9 for the association of PPI use and C. difficile diarrhea. In contrast to PPIs. the specific mechanism has not been clearly elucidated. Improvement in Health Outcomes 20.

Vakil N. 7. Stolle J. pylori-negative. Aliment Pharmacol Ther 2008.77(3–4): 184–197. Am J Gastroenterol 2006. Am J Gastroenterol 2003. Lee C. immunity. Maaroos HI.98(7):1487–1493. Hunt RH. The important negative consequences of long-term therapy with PPIs is a valid concern as there are no studies of use beyond 10 years and only a limited number of studies with relatively few patients have examined other possible effects of long-term gastric acid-suppression treatments. Monnikes H. Malfertheiner P. Schubert ML. 6. Fried M. Fiedorek S. 11. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Kwok A. Dent J. Kalantzis C. Helicobacter 2006. Review article: the long-term use of proton-pump inhibitors.23(6):595–601. Orwoll E. 1):21–25. Bruce mg. Kahrilas P. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Raghunath AS. 14. Shaheen NJ. Huang B. Black E. Modlin IM. Pohl D. Treatments. . vaccines for Helicobacter infection. 4. J Pediatr Gastroenterol Nutr 2005. Castell DO. Calcif Tissue Int 2008.13(Suppl.7(3):271–281. Gut 2005. Johansson S. Forte JG. 1):55–63.Chapter 20 / Gastric Acid Secretions. 5. Chmiela M. 2.135(4):1383–1391. Kandulski A. Helicobacter 2005. Curr Opin Gastroenterol 2007. New algorithm for the treatment of gastro-oesophageal reflux disease. Cell biology of acid secretion by the parietal cell.27(3):249–256. Tolia V. Schoenfeld PS. Clinicians should monitor patients on chronic acid-suppressive therapy for vitamin and mineral status and initiate supplementation before deficiencies develop.27(5):396–403. Jones R. and Nutritional Consequences 495 role of HP infection in acid secretion creates opportunities to manage the root cause of some symptoms such that prevalence of more severe outcomes may be reduced. Fox M. Leong RW. et al. Shaker R. 9. Katelaris P.11(Suppl. et al. and step-down algorithms should be considered. Peura DA. 18. Goke B. O’Morain C.40(8):619–626. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. 3. 20. Dig Liver Dis 2008.22(Suppl. Prinz C. not dysmotility. 16. 10. NSAID/aspirin-negative peptic ulcers. Annu Rev Physiol 2003. Helicobacter pylori eradication therapy: indications. Dent J. RECOMMENDATIONS Long-term use of acid-suppressive therapy should be evaluated at least annually. Wallander MA. Yao X. 13. McColl KE. Gastric secretion. Yu EW. Aliment Pharmacol Ther 2005. Ensrud KE. Thoua NM. immunity. Kahrilas PJ. 8. Expert Opin Drug Saf 2008. Inflammation. et al. 19. HP infection should be ascertained and treated as there are numerous negative consequences associated with this infection. Inflammation. Acid-suppressive medications and risk of bone loss and fracture in older adults. REFERENCES 1. Control of gastric acid secretion in health and disease.101(8):1900–1920.54(5):710–717. McColl K. 1):21–26. Acid-related oesophageal sensitivity. Hillier TA. Lam T. Andersen LP. Hiltz SW. Emmanuel AV. Do we need gastric acid? Digestion 2008. Epidemiology of Helicobacter pylori infection.40(3): 319–327. 12. Gastroenterology 2008. Am J Gastroenterol 2009. Selgrad M.6. Helicobacter 2008. Gold BD. and vaccines for Helicobacter infection. Lane NE.10(Suppl. Holtmann G. Schubert ML. 1):1–6. differentiates subgroups of patients with non-erosive reflux disease. Spechler SJ. Michetti P. Helicobacter pylori infection: a clinical overview. Blackwell T. Epidemiology of gastro-oesophageal reflux disease: a systematic review. et al. et al.134(7): 1842–1860. Efficacy and safety of lansoprazole in adolescents with symptomatic erosive and non-erosive gastroesophageal reflux disease. McLoughlin RC. Gastroenterology 2008. Khoo D. Permin H. Vaezi MF. 17. How I manage H. Tack J. 15.104(1):190–193. Tytgat GN. Malfertheiner P. Aliment Pharmacol Ther 2008.83(4):251–259.65:103–131. El Serag HB. efficacy and safety. van Zanten SV.

J Am Chem Soc 2004. Munson K. . Helicobacter pylori eradication in long-term proton pump inhibitor users in primary care: a randomized controlled trial. Jackson W.134(4):937–944. 36. Masaoka T. J Clin Biochem Nutr 2008. Aliment Pharmacol Ther 2003. 21. double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. World J Gastroenterol 2008. Helicobacter pylori treatment: is sequential or quadruple therapy the answer? Rev Gastroenterol Disord 2008.65(2):264–281. Gornall C.57(Suppl. Best Pract Res Clin Gastroenterol 2001. Shin JM. Ruhl CE. Norton B. Dig Dis Sci 1999. Kidd M. Obesity correlates with gastroesophageal reflux. Gastroenterology 2008. Chemistry of covalent inhibition of the gastric (H+. Konturek JW. El Serag HB. Lacut K. Sun SX. Physician’s Desk Reference: PDR—Nexium Delayed-Release Capsules (AstraZeneca LP). pylori eradication rates in clinical practice by adopting first and second-line regimens proposed by the Maastricht III consensus and a third-line empirical regimen. A century of ulcer medicines. Goldstein JL. Niv Y. Scheindlin S.104(1):21–25. New concepts of resistance in the treatment of Helicobacter pylori infections. Christ G.6(4):393–400. Vakil N. 42. Little AG. Le Gal G. 37.25(5):585–592.496 Part V / Prevention of Major Disabilities. Kania J. Tytgat GN. 32. Lee KY. Contemporary understanding and management of reflux and constipation in the general population and pregnancy: a consensus meeting. 5):125–136. Gastric epithelial cell modality and proton pump inhibitor. Physician’s Desk Reference: PDR—Prevacid Delayed-Release Capsules (TAP). 28. 6-18-2008. Abraham NS. J Physiol Pharmacol 2006.15(3):487–495. 39. Suzuki H. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Nat Clin Pract Gastroenterol Hepatol 2008. Ann Epidemiol 1999. 2008. Siller-Matula JM. Margantinis G. Sechopoulos P. PDR Electronic Library. 46.157(1):148–5. 2008. McColl KE. Improvement in Health Outcomes 20. Gilard M. Le Calvez G. 6-18-2008. K+)-ATPase by proton pump inhibitors. Gillen D. pylori treatment: new wine in old bottles? Am J Gastroenterol 2009. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized. Sachs G. Mutnick JL. Cho YM. Hungin AP. Hampel H. H pylori recurrence after successful eradication.8(2):77–82. Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotective drug prescribing and utilization. 23. 40. J Am Coll Cardiol 2008. The relative efficacies of gastroprotective strategies in chronic users of nonsteroidal anti-inflammatory drugs. 24. Pistiolas D. 29. increases risk of gastroesophageal reflux disease hospitalization: the NHANES I Epidemiologic Followup Study. Overweight.44(11):2290–2294. Tran T. Modlin IM. 30.25(2):143–153. Sachs G. 33. Fraser-Moodie CA. 44. Shin JM. Rokkas T. 22. Molecular mechanisms in therapy of acid-related diseases. McColl KE. 34. Pennathur A.104(1):26–30. Kamm MA. Kreiner G. Ascorbic acid attenuates aspirin-induced gastric damage: role of inducible nitric oxide synthase. PDR Electronic Library. 47. Jilma B. Meta-analysis: the efficacy of over-the-counter gastro-oesophageal reflux disease therapies. et al. Arnaud B.5(4):201–206. Clin Gastroenterol Hepatol 2008. Graham DY. Persistent heartburn in a patient on proton-pump inhibitor. Mason J. Scand J Gastroenterol 1999. Cell Mol Life Sci 2008. 26. 35. Muller-Lissner S. H. Weight loss has an independent beneficial effect on symptoms of gastro-oesophageal reflux in patients who are overweight. Robotis I. Leung S. Everhart JE. Metge CJ. Weale AR. Konturek PC. Am J Gastroenterol 2009. Am J Gastroenterol. Aliment Pharmacol Ther 2007. 41. Effect of proton pump inhibitors on vitamins and iron. Cornily JC.143(3):199–211. 38. First National Health and Nutrition Examination Survey. Berstad A.23(8):1859–1866. Fass R. Am Heart J 2009. et al. Targownik LE. 27.104:S5–S9. but not high dietary fat intake. Ann Intern Med 2005.9(7):424–435. Hahn EG. Vagin O. Bertram CT. 6-18-2008. Physician’s Desk Reference: PDR—Aciphex Tablets (Eisai). Aliment Pharmacol Ther 2007. 43.126(25):7800–7811. PDR Electronic Library. 25. 2008. Heading RC. Mol Interv 2005. Curr Med Res Opin 2007. 6-18-2008. 45. Problems related to acid rebound and tachyphylaxis.5(6):321–331.42(3):191–196. Raghunath AS. Lowry AM. PDR Electronic Library. 2008. Hibi T. 2009. Chateau DG.18(3):291–301. Fisher BL. Spiel AO. Magnago S. Vakil N. Scholmerich J.34(4):337–340.51(3):256–260. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Holmes GK. Physician’s Desk Reference: PDR—Zegerid Powder for Oral Solution (Santarus). Cumulative H.14(10):1477–1478. El Serag HB. Shiotani A. 31. Lang IM.

Kelley CM. 49. Heaney RP. 67. Heaney RP. Aliment Pharmacol Ther 2005. Gilmour D. Parkman HP. et al. Proton pump-inhibiting drugs. J Am Coll Nutr 1995. O’Connell MB.Chapter 20 / Gastric Acid Secretions. J Clin Invest 1984. Morawski SG. Fisher RS. 72. 51.66(2):103–108. and Nutritional Consequences 497 48.117(17):579–591. Heaney RP. Marcuard SP.46(5):300–304. Calcif Tissue Int 1990. NJ: Humana Press Inc. Heaney RP.. Salivary uric acid at the acidic pH of the stomach is the principal defense against nitrite-derived reactive species: sparing effects of chlorogenic acid and serum albumin. Helicobacter pylori status. 62. Serfaty-Lacrosniere C. Pietraforte D. Nilius B. Como G. phosphorus. 52. Treatments. Madden DM. and alterations in the intragastric milieu facilitating bacterial N-nitrosation. Liu C. Pedrosa M. Awumey EM. Regional postprandial differences in pH within the stomach and gastroesophageal junction. 53. Calcium in Human Health. Wirz A. 60. Bo-Linn GW. Dig Dis Sci 2004. Henry EB. Calcium in Human Health. Bierman J. 58. Plasma and esophageal mucosal levels of vitamin C: role in the pathogenesis and neoplastic progression of Barrett s esophagus. Hale CA. Ann Intern Med 1994. Menditto A. Fordtran JS. Norkus EP. Sillaber C. Mowat C. . et al. Culbertson VL. Rejnmark L. 74. Khazanie PG. 50. Omeprazole. eds. Scorza G. 63. Cellular functions and fluxes of calcium. J Am Coll Nutr 2001.73(3):640–647. Hoenderop JG. Free Radic Biol Med 2006. Calcium absorption across epithelia. 75. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Carswell A. 66. In: Weaver CM. Sepe TE. Bindels RJ. Wright MJ. Nephrol Dial Transplant 1995. et al. Cady PS. 2006:13–35. 68. Martin IG. Totowa. Santa AC. Recker RR.29(2 Suppl. An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium. Voytko D. Albernaz L.66(5):237–249. Nutrition and gastric cancer risk: an update. Dharmarajan TS.41(12):1753–1763. Hirschowitz BI. 54.120(3):211–215. Davis GR. Wood RJ.89(2):712S–716S. NJ: Humana Press Inc. Buddrus DJ. 69. Heaney RP. Castelli M.37(4):490–493. Murakonda P. Physiol Rev 2005. White KL. histamine H2 receptor antagonists. Saltzman JR. Wien Klin Wochenschr 2005. magnesium or zinc from food in humans. 71. Effect of gastric acid secretion on intestinal phosphate and calcium absorption in normal subjects. Vitamin B12 deficiency. Food Nutr Bull 2008. Green R. Dig Dis Sci 2005. 2006:7–12. Graziani G. Puspok A. Proctor DD. Samoggia P. Ann Pharmacother 2003. 64. Gastroenterology 2000. 65. eds. Long-term proton pump inhibitor therapy and risk of hip fracture. calcium homeostasis. Vo L. Calcium in Human Health. Aliment Pharmacol Ther 2008. Bukoski RD. Gallieni M.22(6):539–545.27(11):1110–1121. McColl KE. Carswell A. Is it time for vitamin B-12 fortification? What are the questions? Am J Clin Nutr 2009. Epstein S. Causes of vitamin B12 and folate deficiency. Russell RM. and bone health. Worthington J. Weaver CM. Force WS.116(4):813–822. Williams C. Proton pump inhibitors. Calcium absorption and achlorhydria. 56.14(4):364–368. Badalamenti S. Insogna KL. eds. Lebelt AS. 57.79(2):76–83. In: Weaver CM. 73.. Dowell SD. 61. Absorbability of calcium sources: the limited role of solubility.10(8):1376–1380. Am J Med 2005. et al. 70. Gastroenterology 1999.313(2):70–73. Wirz A. Proton pump inhibitors reduce the bioavailability of dietary vitamin C.119(2): 339–347.118(7):778–781. Doma S. Bone as the calcium nutrient reserve. Kerstetter JE. 59. Yang YX. Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc 2008.49(6):914– 919. Mohnen J. Fountoulakis A. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Malesci A. Totowa. Murray AM. Hossack M. Lewis JD. Metz DC. McColl KE.):S20–S34. et al. Dixon MF. 55. Meeker AD. Bendich A. JAMA 2006. Heaney RP. Calcif Tissue Int 2006.20(3):239–246.9(3):162–167. Lechner K. Absorbability and cost effectiveness in calcium supplementation. Vestergaard P.85(1):373–422. Carswell A. N Engl J Med 1985. Introduction. Mosekilde L. Nutr Rev 2008. Kerzner LJ. New data on an old theme. Allen LH. Finazzi S. NJ: Humana Press Inc. and other antacid medications and the risk of fracture. Heaney RP.296(24):2947–2953. Cade JE. Ambulatory care increased vitamin B12 requirement associated with chronic acid suppression therapy. Mowat C. Fodinger M. Gillen D. Metere A. Omeprazole and dietary nitrate independently affect levels of vitamin C and nitrite in gastric juice. Simonian HP. Heaney RP. Force RW. Fyffe V. Kanagala MR. Totowa. Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors. Hypochlorhydria from short-term omeprazole treatment does not inhibit intestinal absorption of calcium. Sue-Ling HM. Nutr Rev 2008. Recker RR.. Weaver CM. 2006:1–3.50(12):2276–2285. Grisold W. In: Weaver CM.

Hurrell RF. Use of proton pump inhibitors and risk of osteoporosis-related fractures. Annu Rev Nutr 2001. 93. 83. 105. 84. Kelsey JL.56(9):1291–1295. Frederiksen H. Role of gastric acid in food iron absorption. Ronkainen J. Kim D. Proton pump inhibitor use and enteric infections. Berna MJ. Bothwell T. Manoukian C. J Nutr 2006.76(2):639–645. CMAJ 2008. J Lab Clin Med 1978. Dial S. 79. Al Tureihi FI. Girardi LS.93(9):1409–1415. The importance of gastric hydrochloric acid in the absorption of nonheme food iron. et al. Metge CJ. Gyr K. Wolf-Klein G.117(5):e817-e820. Jensen TG. Juillerat M. O Brien LA. Hip Fracture Study Group. Malamisura B. Sidney S. Richards JB. length of stay. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. 89.171(1):33–38. Cucino C. Bille J. Proton pump inhibitors: balancing the benefits and potential fracture risks. Holm A. Bezwoda W. Stewart CL. et al. 100. 86. Gut 1996. Goltzman D. pylori-negative duodenal ulcer prevalence and causes in 774 patients. Engstrand L. et al.6(3):239–243. Shin WG. Am J Gastroenterol.294(23):2989–2995. et al. Autoimmune gastritis in type 1 diabetes: a clinically oriented review. De Block CE. 94. Isenberg H.39(1):54–59. Gulmez SE.85(6):295–330. Meat protein fractions enhance nonheme iron absorption in humans. Helicobacter 2001.145(9):786–793. Zimmermann MB. Laine L. 96. JAMA 2005. Cantero J. 91. Influence of gastric acid on susceptibility to infection with ingested bacterial pathogens. 87. Dale B. Leung S.28(1):96–107. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Charlton R.17(12):1503–1506. Targownik LE. Hallas J. J Clin Endocrinol Metab 2008. Kim KO.179(4):306–307. Hassoun A. Undy B. Has peptic ulcer disease changed during the past ten years in Korea? A prospective multi-center study.167(9):950–955. Nutritional iron deficiency. 80. Huang A. et al. Dial MS. CMAJ 2008. 101. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. et al. Blanco M. 81.179(4):319–326. Cunningham R. Powell JJ. Am J Epidemiol 1997. 104.21:1–21. 103. Saraga E. Has the impact of Helicobacter pylori therapy on ulcer recurrence in the United States been overstated? A meta-analysis of rigorously designed trials. Bolling-Sternevald E. Hoffmann KM. Greco S. Lix LM. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Kozlov S. Serrano J. Jensen RT. Hunt RH. Am J Gastroenterol 1998. H. De Leeuw IH. Grisso JA. Arch Intern Med 2007. Thorens J. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. Menzies D. Fernandez-Salazar L. Delaney JA. Jang HJ. Liu Q. Brody T. Gaunt N. Aliment Pharmacol Ther 2003. . 82.498 Part V / Prevention of Major Disabilities. et al. Dig Dis Sci 1999. Hartland EL. Van Gaal LF. Kim KH. Pedersen C. Gut 2007. Am J Epidemiol 2006. Howden CW. Crisp ML.104:S10–S16. Brown GM. Perspectives on nutritional iron deficiency. 1999:693–878. Rood JI. and proton pump inhibitors: key factors in Clostridium difficile-associated disease in nursing home patients. 99. Pediatrics 2006. Mayet F. et al. Bargiggia S. Dig Dis Sci 2008. Inorganic nutrients. Hurrell RF. Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization. Vieth M. Barkun AN. Pastore L. 77. Risk factors for hip fracture in men. Bomford A. Albumin. Lynch SR. Aro P. Serum gastrin in Zollinger-Ellison syndrome: I. Terrin G. Nutritional Biochemistry. 97. Proc Natl Acad Sci U S A 2009. Parente F.6(2):105–108. Tennant SM. Lawrence Z. Fernandez-Bermejo M. 92. Cirillo P.92(1):108–116. 95. 85. Maislin G. Lancet 2007. 88. Romano C. Valberg LS. Hutchinson C. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Chung YW. et al. Canani RB. Improvement in Health Outcomes 76.53(6):1527–1531. Hospital use of acid-suppressive medications and its fall-out on prescribing in general practice: a 1-month survey. Cook JD. The effect of achylia gastrica on iron absorption. Phumoonna T. Mateos JM. Gastroenterology 1981. Lyras D. Hopkins RJ. Gut 1987. Elitsur Y. 102.43:1185–1191. Leslie WD.44(11):2295–2302. Suissa S. Dial S. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study.136(11):2808–2812. 90. Robins-Browne RM. Medicine (Baltimore) 2006. Schwizer W. Relationship between gastric secretion and infection. 2009. Infect Immun 2008. London: Academic Press. Storskrubb T.93(2):363–371. Gibril F.370(9586):511–520. Prior HJ. Skikne BS. J Clin Invest 1964. Cook JD. Roux KJ. Geissler CA. Reddy MB. Gallus S. Choi MH. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. 98.163(11):1025–1034. Alrasadi K. 78. CMAJ 2004. J Hosp Infect 2003. Non-Helicobacter pylori related duodenal ulcer disease in children. Hallberg L.81(6):1068–1071. Cook JD. Peptic ulcer disease in a general adult population: the Kalixanda study: a random population-based study. Froehlich F. Torrance J. J Am Med Dir Assoc 2005. Gisbert JP. Roggero P.54(3):243–245. Miles CG.

Ann Pharmacother 2002. 107.15(6):1083–1094. Page RL. Ruscin JM. 109. Proton pump inhibitors and Helicobacter pylori gastritis: friends or foes? Basic Clin Pharmacol Toxicol 2006. 108. Valuck RJ. Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor. and Nutritional Consequences 499 106. AstraZeneca. 6-18-2008. Brenner H. Prevalence of chronic atrophic gastritis in different parts of the world.36(5):812–816. Package Insert. Weck MN. . Kuipers EJ. PDR Electronic Library. 110. Cancer Epidemiol Biomarkers Prev 2006. 2008. Prilosec Package Insert (omeprazole and omeprazole magnesium).99(3):187–194. Treatments. Physician’s Desk Reference: PDR—Protonix Tablets (Wyeth). 2009.Chapter 20 / Gastric Acid Secretions.

You're Reading a Free Preview

Download
scribd
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->