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  • Clinical effects of proton pump inhibitors

    Focus on pharmacogenetics, kinetics and dynamics

    Nicole G.M. Hunfeld

  • Promotiereeks HagaZiekenhuis

    Het HagaZiekenhuis van Den Haag is trots op medewerkers die fundamentele bijdragen leveren aan de wetenschap en stimuleert hen daartoe. Om die reden biedt het HagaZiekenhuis zijn promovendi de mogelijkheid hun dissertatie te publiceren in een speciale Haga uitgave, die onderdeel is van de promotiereeks van het HagaZiekenhuis. Daarnaast kunnen promovendi van het HagaZiekenhuis in het wetenschaps magazine HagaScoop van het ziekenhuis aan het woord komen over hun promotieonderzoek.

  • Clinical effects of proton pump inhibitors

    Focus on pharmacogenetics, kinetics and dynamics

    Nicole G.M. Hunfeld

  • Clinical effects of proton pump inhibitors

    Nicole G.M. Hunfeld

    2010 Den Haag

    ISBN: 978-90-9025656-6

    Graphic DesignSaskia Janssen

    Pre-pressDe VormCompagnie, Houten

    PrintingDrukkerij Badoux

  • Proefschrift

    ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam

    op gezag van de rector magnificusProf.dr. H.G. Schmidt

    en volgens besluit van het College voor Promoties

    De openbare verdediging zal plaatsvinden op vrijdag 24 september 2010 om 9.30 uur


    Nicole Geertruida Maria Hunfeldgeboren te Waalwijk

    Klinische effecten van proton pomp remmers

    Focus op farmacogenetica, kinetiek en dynamiek

    Clinical effects of proton pump inhibitors

    Focus on pharmacogenetics, kinetics and dynamics

  • Promotiecommissie

    Promotor: Prof.dr. E.J. Kuipers

    Overige leden: Dr. T. van Gelder Prof.dr. C.J.J. Mulder Prof.dr. M.C.J.M. Sturkenboom

    Copromotor: Dr. W.P. Geus

  • Printing of this thesis is financially supported by:Apotheek Haagse Ziekenhuizen, AstraZeneca B.V., Bayer Schering Pharma, Fresenius-Kabi B.V., HagaZiekenhuis, Inge Voesten-Appel stichting and Nederlandse Vereniging voor Gastroenterologie

  • Contents

  • Chapter 1 General introduction 2

    Chapter 2 Rebound acid hypersecretion after therapy with proton pump inhibitors


    Chapter 3 Genetic polymorphisms of CYP2C19 in a Dutch population


    Chapter 4 Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians


    Chapter 5 A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism


    Chapter 6 A comparison of the acid-inhibitory effects of esomeprazole and rabeprazole in relation to CYP2C19 polymorphism


    Chapter 7 Determination of rabeprazole and metabolite in human serum using high-speed HPLC


    Chapter 8 Systematic review: the influence of CYP2C19 polymorphism on the acid-inhibitory effects of proton pump inhibitors


    Chapter 9 General discussion 122

    Chapter 10 Summary 136

    Appendices Samenvatting voor niet-ingewijden 144

    Dankwoord 152

    List of publications 156

    Over de auteur 158

  • Chapter 1

  • General introduction

  • 1

  • mmm 11

    General introduction1Acid-related diseasesAcid-related diseases, including gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and dyspepsia are common. Of every 1000 patients visiting a general practitioner in the Netherlands, 34 do so because of upper gastro intestinal symptoms [1]. These symptoms include heartburn, acid regurgitation, abdominal or retrosternal discomfort or pain, bloating, nausea, globus feeling, and dysphagia. It is estimated that 20-30% of these symptoms are caused by GERD, about 5% by peptic ulcer disease and less than 1% by a malignancy [2]. In 60 to 70% of the patients, no pathophysiological cause is identified and these patients are often classified as having functional upper GI symptoms. Because of their persistent or recurrent natural history, the acid-related disorders are associated both with diminished quality of life and significant morbidity [3].

    Gastro-oesophageal reflux diseaseGastro-oesophageal reflux disease is a condition characterized by pathologic reflux from the stomach into the oesophagus leading to symptoms and/or esophageal lesions. It comprises a wide spectrum of disorders, ranging from gastro-oesophageal reflux without significant clinical or pathological impact, through to the more severe complications of reflux disease, including erosive oesophagitis, Barretts oesophagus and oesophageal adenocarcinoma [4]. Symptoms considered to be related to reflux of gastric contents into the oesophagus are common in the general population. The typical symptoms of GERD in adult patients are retrosternal or sub-sternal burning, regurgitation, epi-gastric pain and dysphagia. The atypical symptoms include belching, water brash, wheezing and cough. These symptoms appear to be more commonly experienced in developed countries, although their incidence and prevalence now appear to be increasing in parts of the world where they were previously uncommon, particularly South-East Asia and the Far East. In Western populations it is estimated that one in four persons experiences heartburn or acid regurgitation at least once a month, 12% at least once per week and 5% on a daily basis [5].

    Peptic ulcer disease A peptic ulcer is a defect in the gastric or duodenal mucosa that extends into the muscularis mucosae. Peptic ulcers occur mainly in the stomach (gastric ulcer; GU) or proximal duodenum (duodenal ulcer; DU). PUD develops when the protective mechanisms of the gastrointestinal mucosa, such as mucus and bicarbonate secretion, are overwhelmed by the damaging effects of gastric acid and pepsin. Two decades ago, Helicobacter pylori (H. pylori) infection was identified as the main cause of PUD. Management of H. pylori-associated PUD has improved radically since then. As the prevalence of H. pylori infection has declined in Western countries, GU has become more commonly associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA). In the Netherlands, the incidence of gastric ulcers decreased between 1992 and 2003 from 18.3 to 6.8/100,000 in men and from 13.0 to 5.1/100,000 in women [6]. However, prescriptions for drugs implicated in the aetiology of PUD, such as aspirin and NSAIDs, have also increased over this time period [7]. Individuals with PUD are at risk of developing complications such as gastroduodenal haemorrhage, perforation and obstruction. Mortality among patients with these complications is high. According to Dutch guidelines, patients with risk-factors (age > 70 years, PUD, ongoing H. pylori infection, use of anticoagulants, severe rheumatoid arthritis, heart failure, diabetes, high dose NSAID, use of corticosteroids and/or SSRIs) using NSAIDs or ASA should be prescribed a gastroprotective drug [8]. Still, adherence to gastroprotection for prevention of NSAID-induced PUD remains far from optimal [9].

  • 12 mmm

    DyspepsiaDyspepsia is a chronic or recurrent pain or discomfort centered in the upper abdomen. Discomfort is defined as a subjective negative feeling that is nonpainful, and can incorporate a variety of symptoms including early satiety or upper abdominal fullness. Frequent reflux symptoms (twice a week or more) probably impair quality of life and are generally considered to identify GERD until proven otherwise [10]. In the Netherlands, 150 new dyspeptic patients present at general practices annually [11].


    AntacidsAntacids are alkali preparations that neutralize hydrochloric acid in the stomach. Antacids can contain aluminium, magnesium, calcium or combined substances. Antacids are indicated for dyspepsia, GERD, reflux oesophagitis and gastritis. Their onset of action is fast, but they require frequent administration (4 to 6 times a day) because of their short duration of action [12, 13].

    H2-receptor antagonistsParietal cells in the stomach express receptors for acetylcholine, gastrin and histamine. Stimulation of these receptors results in gastric acid production. H2-receptor antagonists (H2RAs) inhibit acid production by reversibly competing with histamine for binding to H2-receptors on the parietal cells. Four different H2RAs are available: cimetidine, famotidine, nizatidine and ranitidine. H2RAs are indicated for reflux-oesophagitis, ulcus duodeni, ulcus ventriculi, prevention of recurrent peptic ulcers and the treatment of NSAID related ulcers. These agents are primarily effective in decreasing basal acid production and nocturnal acid breakthrough. They are however less effective in controlling food-stimulated acid secretion during daytime. In general, H2RAs are administered twice a day. Although H2RAs have reasonable efficacy, patients develop tolerance in particular with continuous therapy [12-15].

    Proton pump inhibitors Proton pump inhibitors (PPIs) suppress gastric acid secretion by specific inhibition of the H+/K+- ATPase in the gastric parietal cell. This process starts with absorption of the PPI in the parietal cell. PPIs are weak bases, so protonation takes place in the acidic region of the secretory canaliculus of the parietal cell. In the secretory canaliculus, the methylsulfinylgroup shifts to a highly reactive sulfenamide. The final step is covalent binding of the reactive sulfenamide to 2 cysteine moieties of the catalytic subunit of the H+/K+-ATPase of the proton pump. This results in inhibition of the acid secretion, followed by elevation of the intragastric pH [16]. PPIs are indicated for the treatment of GERD, reflux oesophagitis, peptic ulcers and Zollinger-Ellison syndrome. In addition, PPIs are used for