ReviewProton pump inhibitors in GORD: An overview of their pharmacology, efficacy and safety
Section snippets
Regulation of acid secretion
Gastric acid secretion is under nervous and hormonal influence [1]. This physiologic process is controlled by a number of redundant second messenger pathways activated as a result of the binding of gastrin, acetylcholine, histamine, and prostaglandins to the specific receptors on the basolateral surface of parietal cells. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium, whereas that of histamine is mediated by activation of adenylate cyclase
Chemistry and pharmacology of PPIs
Chemically, all the available PPIs [8], [9] consist of a benzimidazole ring and a pyridine ring, but vary in the specific side ring substitution (Fig. 2). They are all weak protonatable pyridines, with a pKa of about 4 for omeprazole and lansoprazole, about 3.9 for pantoprazole, and about 5.0 for rabeprazole. As a result, once drugs have reached the gastric mucosa after systemic absorption, they accumulate specifically and selectively in the secretory canaliculus, the highly acidic space of the
Why are PPIs better antisecretory agents than H2-RAs?
H2-RAs have a relatively short duration of action and, depending on the individual agent and whether the patient is in a fed or fasting state, suppress acid for approximately 4–8 h [14] Consequently, multiple daily doses of these agents are likely to be required. Furthermore, H2-RAs produce incomplete inhibition of post-prandial gastric acid secretion. Overall, these agents inhibit acid secretion by up to 70% over a 24-h period [14], [15].
A further shortcoming is that tolerance to standard H2
Are currently available PPIs all the same?
Although there are differences among PPIs concerning their pharmacokinetics, pharmacodynamics, influence by food and antacids as well as potential for drug interactions [8], [38] it is not always evident whether these often subtle differences are clinically relevant. Several comprehensive analyses of the available clinical trials concluded that – when used at equivalent doses in the treatment of various acid-related disorders – all the available agents are similarly effective [8], [39], [40].
Therapy of gastro-oesophageal reflux disease
According to the recent Montreal definition [52], gastro-oesophageal reflux disease is a chronic condition, which develops when the reflux of stomach contents causes troublesome and recurrent symptoms, which could be typical (i.e. oesophageal) and atypical (i.e. extra-oesophageal), and/or complications. Possible complications include oesophagitis, ulcer, stricture and Barrett's oesophagus.
The aims of treatment of GORD include [53]:
- •
Relief of symptoms and improvement of Quality of Life (QoL).
- •
Short- and long-term safety of proton pump inhibitors
PPIs represent a very effective class of drugs, widely prescribed in all age populations, often to patients with co-morbid conditions (and therefore polymedicated) and, in some instances, for prolonged periods of time. All these factors may challenge their safety profile. However, the tolerability of PPIs in both short- and long-term use has been remarkably good. This safety profile is similar across the various PPIs used in clinical practice. The most common adverse events are represented by
Conclusions
Since their introduction into clinical practice almost two decades ago, PPIs have revolutionized the medical treatment of GORD. The marked progress that has been achieved in symptom resolution and oesophageal mucosal healing has made PPIs the first choice treatment not only for reflux disease but also for other acid-related diseases. Although PPIs are very effective drugs they are still far from the ideal antisecretory compound and display a number of shortcomings mainly due to their intrinsic
Authors’ declaration of personal interests
The authors have received consulting and/or lecture fees from pharmaceutical companies and other organizations. The authors have received research support from charities and government sources at various times. No author has any direct stock holding in any pharmaceutical company.
Acknowledgements
This work was carried out thanks to an unrestricted educational grant from Janssen-Cilag Italy, who supported the meetings amongst the authors. The Company had no role in design, planning or execution of the review, or in writing the manuscript. The terms of the financial support from Janssen-Cilag included freedom for the authors to reach their own conclusions, and an absolute right to publish the results of their work, irrespective of any conclusions reached. Janssen-Cilag did not have the
References (249)
- et al.
Pharmacological control of gastric acid secretion for the treatment of acid-related peptic disease: past, present, and future
Pharmacol Ther
(2003) - et al.
Gastric somatostatin: a paracrine regulator of acid secretion
Metabolism
(1990) - et al.
Pharmacological and pharmacodynamic essentials of H2-receptor antagonists and proton pump inhibitors for the practising physician
Best Pract Res Clin Gastroenterol
(2001) - et al.
Rapid onset of tolerance to beta-agonist bronchodilation
Respir Med
(2005) - et al.
Mechanisms of opioid-induced tolerance and hyperalgesia
Pain Manag Nurs
(2007) - et al.
Twenty-four-hour intragastric pH: tolerance within 5 days of continuous ranitidine administration
Am J Gastroenterol
(2000) Antisecretory drugs, Helicobacter pylori infection and symptom relief in GORD: still an unexplored triangle
Dig Liver Dis
(2005)- et al.
Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough
Gastroenterology
(2002) - et al.
Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors
Am J Gastroenterol
(1998) - et al.
Proton pump inhibitors: the beginning of the end or the end of the beginning?
Curr Opin Pharmacol
(2008)