Proton pump inhibitors: update on their role in acid-related gastrointestinal diseases

Gastric acid is pathogenic in many gastrointestinal disorders, such as gastroesophageal reflux disease and peptic ulcer disease. Proton pump inhibitors (PPIs) are the antisecretory drugs of choice for serious acid-related conditions. Ample recent data exist to explicate virtually every aspect of the clinical management of acid-peptic disorders with PPIs. Although all PPIs are effective, there are some differences in their clinical performance, particularly in terms of the degree and speed of gastric acid suppression. Rapid onset of acid suppression may be particularly relevant to newer approaches, such as 'on-demand' or intermittent therapy for non-erosive reflux disease and shorter regimens for Helicobacter pylori eradication. New data, in addition, highlight differences in PPI metabolism that may both affect efficacy and predispose patients to drug-drug interactions. PPI selection should involve the awareness of these issues.     

Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases

Current therapies to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and other acid-related diseases either prevent stimulation of the parietal cell (H2 receptor antagonists, H2RAs) or inhibit gastric H+,K+-ATPase (e.g., proton pump inhibitors, PPIs). Of the 2 approaches, the inhibition of the final step in acid production by PPIs provides more effective relief of symptoms and healing. Despite the documented efficacy of the PPIs, therapeutic doses have a gradual onset of effect and do not provide complete symptom relief in all patients. There is scope for further improvements in acid suppressive therapy to maximize healing and offer more complete symptom relief. It is unlikely that cholecystokinin2 (CCK2, gastrin) receptor antagonists, a class in clinical trials, will be superior to H2RAs or PPIs. However, a new class of acid suppressant, the potassium-competitive acid blockers (P-CABs), is undergoing clinical trials in GERD and other acid-related diseases. These drugs block gastric H+,K+-ATPase by reversible and K+-competitive ionic binding. After oral doses, P-CABs rapidly achieve high plasma concentrations and have linear, dose-dependent pharmacokinetics. The pharmacodynamic properties reflect the pharmacokinetics of this group (i.e., the effect on acid secretion is correlated with plasma concentrations). These agents dose dependently inhibit gastric acid secretion with a fast onset of action and have similar effects after single and repeated doses (i.e., full effect from the first dose). Animal studies comparing P-CABs with PPIs suggest some important pharmacodynamic differences (e.g., faster and better control of 24-hr intragastric acidity). Studies in humans comparing PPIs with P-CABs will help to define the place of this new class in the management of acid-related diseases.     

The proton-pump inhibitors: similarities and differences

OBJECTIVE: This paper examines the clinical pharmacology of the proton-pump inhibitors (PPIs) and briefly reviews some comparative studies of these agents. BACKGROUND: PPIs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. Although these drugs-omeprazole, lansoprazole, pantoprazole, and rabeprazole-share a common structure (all are substituted benzimidazoles) and mode of action (inhibition of H+,K+-adenosine triphosphatase [ATPase]), each differs somewhat in its clinical pharmacology. RESULTS: In comparative clinical trials found in MEDLINE, PPIs administered once daily produced endoscopic evidence of healing in >90% of patients with duodenal ulcer after 4 weeks of treatment, in >90% of those with gastric ulcer after 6 weeks of treatment, and in >90% of those with ulcerative or erosive GERD after 8 weeks of treatment. Maintenance therapy with daily doses of a PPI has been shown to be an effective means of preventing GERD relapse. PPIs also inhibit the growth of Helicobacter pylori, now recognized as an important factor in peptic ulcer disease, and, when administered in combination with antibiotics, provide the best treatment for eradication of the bacterium. Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and, compared with omeprazole, a greater effect on intragastric pH after the first dose. Omeprazole and lansoprazole have a greater potential for drug-drug interactions than do pantoprazole and rabeprazole. CONCLUSION: Although the individual PPIs have similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen.     

A review of omeprazole use in the treatment of acid-related disorders in children

BACKGROUND: Acid peptic disease is a common problem, with a similar prevalence of gastroesophageal reflux disease (GERD) in adults and children. The presentation of GERD in infants and children varies from crying, irritability, or sleep disturbance to feeding difficulties, vomiting, or rumination. Helicobacter pylori (HP)-related diseases and gastric and duodenal ulcers are much more common in adults than in children, who are more likely to have gastritis or duodenitis. However, because HP infection is most likely acquired in childhood, treatment of children with endoscopically documented active HP disease may minimize the potential risk for peptic ulcer or gastric cancer in adulthood, although this is yet to be proved. OBJECTIVE: Omeprazole has been shown to be effective in the treatment of acid-related diseases. This paper reviews the literature on the use and administration of omeprazole for the treatment of GERD, peptic ulcer disease, HP infection, and other acid-related conditions in children. METHODS: Studies were identified through searches of MEDLINE and Science Citation Index for the period 1986 to November 2000, and from the reference lists of identified articles. The search terms used included omeprazole, proton pump inhibitor (PPI), children, pediatrics, routes of administration, GERD, HP infection, esophagitis, and administration. In addition, the manufacturer of omeprazole was asked for relevant unpublished information. RESULTS: Marketed and extemporaneous formulations of omeprazole have been administered to children aged 2 months to 18 years for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, HP infection, and related conditions at dosages of 5 to 80 mg/d (0.2-3.5 mg/kg/d) for periods ranging from 14 days to 36 months with a low incidence of adverse effects. The initial dose most consistently reported to heal esophagitis and provide relief of symptoms of GERD appears to be 1 mg/kg per day. CONCLUSIONS: In uncontrolled clinical trials and case reports to date, omeprazole has been effective and well tolerated for the acute and chronic treatment of esophageal and peptic ulcer disease in children, particularly those who had failed to respond to previous treatment with histamine2-receptor antagonists. Should future long-term, controlled clinical trials in children demonstrate safety and efficacy, this PPI is likely to find a place in the armamentarium of pediatric pharmacotherapy.     

Proton Pump Inhibitors: Review of Emerging Concerns

First introduced in 1989, proton pump inhibitors (PPIs) are among the most widely utilized medications worldwide, both in the ambulatory and inpatient clinical settings. The PPIs are currently approved by the US Food and Drug Administration for the management of a variety of gastrointestinal disorders including symptomatic peptic ulcer disease, gastroesophageal reflux disease, and nonulcer dyspepsia as well as for prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy. PPIs inhibit gastric acid secretion, and the most commonly associated adverse effects include abdominal pain, diarrhea, and headache. Although PPIs have had an encouraging safety profile, recent studies regarding the long-term use of PPI medications have noted potential adverse effects, including risk of fractures, pneumonia, Clostridium difficile diarrhea, hypomagnesemia, vitamin B₁₂ deficiency, chronic kidney disease, and dementia. These emerging data have led to subsequent investigations to assess these potential risks in patients receiving long-term PPI therapy. However, most of the published evidence is inadequate to establish a definite association between PPI use and the risk for development of serious adverse effects. Hence, when clinically indicated, PPIs can be prescribed at the lowest effective dose for symptom control.     

急诊老年人酸相关性上消化道出血分析

目的探讨诊老年人与酸相关性上消化道出血的原因及特点。方法对239例与酸相关性老年人消化道出血进行回顾性分析。结果老年人酸相关性上消化道出血占所有上消化道出血的57.87%,其中,胃食管反流病占1.67%,消化性溃疡占63.18%,胃炎或十二指肠球炎占9.21%,功能性消化不良占0.84%,急性胃黏膜病变占25.10%。死亡27例,其中直接死于出血1例,占3.70%,死于全身慢性疾病恶化以及出血后并发症及继发的多脏器功能衰竭24例,占88.89%。病死率占总数的11.30%。结论酸相关性疾病是老年人上消化道出血的主要原因,影响预后的因素更倾向于基础疾病及全身状况的恶化。      

Developments in the inhibition of gastric acid secretion

Understanding the physiology of gastric acid secretion and the pathophysiology of acid-related diseases (e.g. gastrooesophageal reflux and peptic ulcer) has led to the development of numerous ways to decrease acid exposure. Pharmacologically one can try to neutralize secreted acid by antacids, prevent stimulation of the parietal cell, improve mucosal defences and block the functioning of the proton pump. Proton pump inhibitors (PPIs) inhibit the final step of acid secretion, and are currently the most potent acid inhibitors. Major therapeutic improvement within the PPI class appears unlikely, as agents in this class share similar chemistry, mode of action, and pharmacokinetic profiles. New approaches that block acid secretion are now being developed. Gastrin (CCK2) receptor antagonists and potassium-competitive acid blockers (P-CABs) are in clinical development.     

Proton pump inhibitors and hospital discharge rates for gastrointestinal events in Italy: a national ecological study

BACKGROUND: Several meta-analyses have supported the efficacy of proton pump inhibitors (PPIs) both in the treatment of peptic ulcers and in the prevention of ulceration, perforation, and hemorrhage from the upper gastrointestinal tract. PPIs have been associated with reducing the risk for recurrent ulcer bleeding and ulcer-related surgery, but they have not been associated with reduced mortality rate. OBJECTIVES: The aim of the current analysis was to conduct a national ecological study exploring the relationship between the consumption of PPIs and hospital discharge rates for gastrointestinal events. We also analyzed the potential savings for the Italian National Health Service (INHS) obtained by a reduction in hospitalizations for gastrointestinal events. METHODS: Data provided by the Italian Ministry of Health allowed us to calculate the annual number of hospital discharge rates from 2000 to 2003 for gastrointestinal events and the national expenditure and consumption rates (expressed as defined daily doses [DDDs] per 1000 population per day) for histamine-2-receptor antagonists, prostaglandins, PPIs, and for other drugs prescribed for peptic ulcer and gastroesophageal reflux disease. RESULTS: The results of this study suggest that there was a statistically significant relationship between the rate of hospital discharge for gastrointestinal events and PPI consumption r = -0.99; P = 0.003). An estimated mean increase of 180.8% in the number of DDDs for PPIs was found among all Italian regions. This drug's consumption increase was associated with an increase of 61.1% in the drug expenditure for treatment of peptic ulcer and gastroesophageal reflux diseases. At the same time, there was a 23.3% reduction in hospital discharge rates for gastrointestinal events and a reduction of 24.5% in the expenditure sustained by INHS for reimbursement of diagnosis-related group tariffs. In Italy there was an absolute increase of 353 Euro million in the expenditure for gastroprotective drugs and a reduction of 39.6 million Euro in the expenditure for reimbursements due to hospitalization for gastrointestinal events. CONCLUSIONS: Based on the results of this study in the Italian population, an increase of PPI consumption was observed to coincide with a reduction of hospital admissions for gastrointestinal events. Although this was not a cost-effectiveness analysis, and some relevant societal costs were not considered, this study found that for each 1000 Euro spent for gastroprotective drugs a reduction of 112 Euro was observed in the expenditure for hospital admissions due to gastrointestinal events. This finding also suggests that there is room for improvement in the utilization of PPIs for public health protection in Italy.     

Proton pump inhibitors: an update

Since their introduction in the late 1980s, proton pump inhibitors have demonstrated gastric acid suppression superior to that of histamine H2-receptor blockers. Proton pump inhibitors have enabled improved treatment of various acid-peptic disorders, including gastroesophageal reflux disease, peptic ulcer disease, and nonsteroidal antiinflammatory drug-induced gastropathy. Proton pump inhibitors have minimal side effects and few significant drug interactions, and they are generally considered safe for long-term treatment. The proton pump inhibitors omeprazole, lansoprazole, rabeprazole, and the recently approved esomeprazole appear to have similar efficacy.     

An overview of proton pump inhibitors.

SUMMARY: Proton pump inhibitors are the standard of treatment for acid-related disorders. These disorders include gastroesophageal reflux disease and its complications (i.e., erosive esophagitis and Barrett's esophagus), peptic ulcer disease, Zollinger-Ellison syndrome, and idiopathic hypersecretion. Proton pump inhibitors are also successfully used for the treatment of Helicobacter pylori infection and upper gastrointestinal bleeding.There are currently five proton pump inhibitors approved by the Food and Drug Administration and available in the United States. These are omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), and esomeprazole (Nexium). This review discusses the history of proton pump inhibitors and compares and evaluates the pharmacology including mechanism of action, pharmacokinetics, pharmacodynamics, administration, dosage, and drug interactions. Information regarding therapeutic indications, clinical efficacy, short- and long-term side effects, and cost is also presented. A case presentation offers an analysis of the use of proton pump inhibitors in individualized patient care.     

长期使用质子泵抑制剂对肠道菌群的影响

目的观察胃食管反流病和消化性溃疡患者长期使用质子泵抑制剂治疗后肠道菌群变化。方法选取胃食管反流病及消化性溃疡患者60例（观察组）,口服奥美拉唑,20mg,每日2次,疗程8周;选取健康志愿者20例（对照组）;利用实时荧光定量聚合酶链反应（PCR）检测观察组患者服药前、服药后4周、8周及对照组健康者清晨粪便中大肠杆菌、肠球菌属、双歧杆菌属及乳酸杆菌属数量,并对各目标菌群数量进行比较分析。结果与对照组相比,观察组患者服药前及服药后4周粪便中4种目标菌群无明显变化（P〉0.05）,服药后8周,粪便中大肠杆菌（4.81±0.77）lonN/g及肠球菌属（5.24±0.63）lonN/g仍无显著变化（P〉0.05）,但双歧杆菌属（8.82±0.91）lonN/g及乳酸杆菌属（6.99±0.69）lonN/g明显减少（P〈0.05）。结论长期服用质子泵抑制剂后可致肠道双歧杆菌属及乳酸杆菌属数量明显下降,使肠道生物屏障受损,增加了肠源性感染风险。     

Ulcer and gastritis

The literature on peptic ulcer and gastritis in 2000 again focused on the topics of Helicobacter pylori, nonsteroidal anti-inflammatory drugs (NSAIDs), and gastric cancer. New diagnostic tests for H. pylori infection have been evaluated, and rescue therapies for failed H. pylori eradication have been tested. The causal relationship between H. pylori infection and nonulcer dyspepsia, gastric cancer, gastroesophageal reflux disease, and NSAID-related ulcers remained heated topics of debate. In 2000, landmark clinical trials and meta-analyses were published addressing these issues. The role of endoscopy in managing nonulcer dyspepsia was better defined. The role of H. pylori eradication in NSAID/aspirin users was reexamined in high-risk patients. Clinical benefit was finally confirmed for specific inhibitors of cyclooxygenase-2 (COX-2). The millennium year turned out to be a very important one in the advancement of knowledge in this field.     

Ulcers and gastritis

This article reviews recently published literature regarding ulcers and gastritis. Although endoscopy is the most useful procedure for diagnosis in the upper gastrointestinal tract, complications do occur, and procedure-related costs are significant. The appropriate indication for endoscopy has recently been debated. Helicobacter pylori is known to be an important pathogen involved in gastric and duodenal inflammation. Peptic ulcer disease and severe gastric mucosal injury are caused by virulent strains, and many reports have focused on CagA. Follow-up studies on surveillance endoscopy in patients with peptic ulcer or gastritis report that patients with atrophic gastritis and intestinal metaplasia are at significantly higher risk for gastric cancer. H. pylori eradication sometimes causes gastroduodenal erosion and reflux esophagitis, and the mechanisms involved have been revealed. Proton-pump inhibitors are useful in the treatment of ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs), reflux esophagitis, and for preventing rebleeding after endoscopic hemostasis, but the effect of long-term acid suppression on the gastric mucosa is still a matter of debate. H. pylori infection and NSAID intake are both risk factors for peptic ulcer disease, and are important aspects in this field.     

Appropriate choice of proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal damage

Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal adverse effects, ranging from dyspepsia and peptic ulcer disease to more serious complications such as haemorrhage or perforation. NSAID-induced gastrointestinal toxicity is a significant medical problem worldwide. Misoprostol is effective in reducing NSAID-induced mucosal damage, but patient compliance is limited by poor tolerance. Histamine receptor antagonists are relatively effective against duodenal ulcers but offer no significant protection against gastric ulcers. Proton pump inhibitors (PPIs), such as pantoprazole, omeprazole and lansoprazole, have been shown to be effective in preventing the development of gastric and duodenal ulcers in high-risk patients taking NSAIDs. PPI therapy is also beneficial in healing NSAID-induced ulcers and preventing their recurrence in patients requiring ongoing NSAID therapy. PPIs have an excellent safety profile, and pantoprazole--with its low potential for drug-drug interactions--is particularly suitable for administration to elderly patients who often require concomitant treatment with other medications.     

Gastric epithelial cell modality and proton pump inhibitor

Proton pump inhibitors (PPIs) are now commonly used for the treatment of acid related diseases such as peptic ulcer and reflux esophagitis. Because of their ability to produce direct inhibition of the proton pump, PPIs provide more sustained increase of the gastric pH than H(2)-receptor (H(2)R) antagonists. Diverse reports have been published on gastric epithelial cell modality associated with PPI treatment both in animal models and clinical settings. The present review summarizes the recent accumulated evidence on gastric epithelial cell modality associated with PPI treatment, including the formation of gastric carcinoid tumors and fundic gland polyps, and the development of gastric mucosal atrophy. Long-term PPI treatment has been reported to cause enlargement of the parietal cells and enterochromaffin-like cells, and to decrease the number of chief cells without affecting A-like cell. Although the development of gastric carcinoid tumors after chronic PPI treatment has been reported in animal studies, no such occurrences have been demonstrated in humans. The effect of PPIs on the formation of fundic gland polyps and the development of atrophic gastritis should be investigated in future studies.     

Proton pump inhibitor-induced hypomagnesemia complicated with serious cardiac arrhythmias

Introduction: Magnesium is the third most common intracellular ion after potassium and calcium and is an important element in the functions of the body, since it participates in more than 300 enzyme systems. It also, plays a significant role in the transport of calcium and potassium across the cell membranes and protects against cardiac arrhythmias and is useful for their treatment due to hypomagnesemia induced from the proton pump inhibitors (PPIs).

Areas covered: PPIs are used for the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD), but have been associated with hypomagnesemia with serious cardiac arrhythmias including torsades de pointes (TdP). To better understand the magnitude of this problem, a Medline search of the English language literature was conducted from 2010 to 2018 and 35 papers with pertinent information were selected.

Expert commentary: The review of these papers suggests that PPIs cause hypomagnesemia, which could be associated with serious cardiac arrhythmias including TdP. However, its incidence is not very common considering the millions of people taking PPIs, but the FDA has advised the physicians to be watchful about this serious adverse effect of PPIs and check the magnesium levels before initiation of PPI treatment.     

The degree of gastroesophageal reflux during treatment of the exacerbation of duodenal peptic ulcer by various drugs

Values of intraesophageal pH, basal fundal pH and hydrochloric acid debit were studied in 73 patients with exacerbation of peptic ulcer on the first days of exacerbation and 2-4 weeks after the initiation of therapy with various drugs. Gastrozepin and cimetidine in parallel with gastric acidity inhibition reduced regularly and considerably a degree of gastroesophageal reflux in the patients. The action of combined vicalin and almagel therapy was manifested later on and was less marked.     

Noninvasive diagnosis of chronic atrophic gastritis by serology

The authors describe a current approach to the laboratory diagnosis of chronic gastritis, by using the plates of serological tests: pepsinogen I (PG-I), gastrin 17, and antibodies to Helicobacter pylori (HP). These tests and a questionnaire were used to examine 168 persons aged 45-70 years, who were a random population sample. Almost a fourth of the adult population was observed to have pronounced gastric mucosal atrophic changes, which might be associated with the high prevalence of HP infection. The concentration of PG-I is high in the persons infected with HP, its cytotoxic strains in particular, its elevated level servers as a valid marker of peptic ulcer disease and gastroesophageal reflux.     

Role of Helicobacter pylori in cirrhotic patients with dyspepsia: a 13C-urea breath test study

The role ofHelicobacter pylori in dyspeptic, cirrhotic patients remains unclear. This prospective outpatient study, conducted to assess the relationship of gastroduodenal disease andH. pylori as determined by the (¹³C) urea breath test, enrolled 109 consecutive cirrhotic patients with dyspepsia. All patients underwent upper-gastrointestinal endoscopy, which revealed respective prevalences of peptic ulcer, gastric ulcer, and duodenal ulcer of 41.3%, 23.9%, and 22.9%;H. pylori infection was found in 52.3%. The rate of peptic ulcer disease in theH. pylori-positive (45.6%) and -negative (36.5%) groups was not significantly different; neither was the prevalence ofH. pylori in patients with or without portal hypertensive gastropathy and with or without esophageal varices. The relationship between peptic ulcer disease andH. pylori in dyspeptic patients with cirrhosis appears to be weak. Likewise, no significant relationship was evident betweenH. pylori and portal hypertensive gastropathy or esophageal varices. This organism may not be a major pathogenetic factor in gastroduodenal diseases in dyspeptic patients with cirrhosis.     

胆汁反流和幽门螺杆菌感染在胆汁反流性胃炎和消化性溃疡发病中的作用

目的探讨胆汁反流和幽门螺杆菌感染在胆汁反流性胃炎和消化性溃疡发病中的作用。方法采用病理组织学检查和快速尿素酶试验对76例胆汁反流性胃炎及22例兼有胆汁反流性胃炎和消化性溃疡的患者行幽门螺杆菌检测,并与29例消化性溃疡患者作对照。结果胆汁反流性胃炎组幽门螺杆菌阳性率为31.6%(24/76例),兼有胆汁反流性胃炎和消化性溃疡组幽门螺杆菌阳性率为59.0%(13/22例),消化性溃疡组幽门螺杆菌阳性率为72.4%(21/29例),前二组比较,差异有显著意义(P<0.05),后二组比较,差异无显著意义(P>0.05)。结论胆汁反流在胆汁反流性胃炎的发病中起主要作用,幽门螺杆菌感染在消化性溃疡的发病中起主要作用。胆汁反流和幽门螺杆菌感染在胆汁反流性胃炎和消化性溃疡的共同发病中互不明显影响,幽门螺杆菌感染所起的作用可能更大一些。