Proton pump inhibitors PPIs

This class of drugs inactivates the H+/K+ ATPase (proton pump) in parietal cells, which is the final common pathway for acid production. Omeprazole was the first preparation to be used in clinical practice and esomeprazole, lansoprazole, pantoprazole and rabeprazole were subsequently introduced. All are similar in efficacy and mode of action.


Omeprazole is a prodrug, in common with all PPIs. It enters the parietal cell from the blood by nonionic diffusion but becomes ionised in the acid milieu around the secretory canaliculus, where it is trapped and concentrated. In this form it is a highly chemically reactive species which binds to sulphydryl groups on Na+/K+ ATPase. This irreversibly inactivates the enzyme causing profound inhibition of acid secretion: a single 20 mg dose reduces gastric acid output by 90% over 24 h. Omeprazole is degraded at low pH and must be given in enteric-coated granules. Systemic availability increases with dose and also with time, due to decreased inactivation of the prodrug as gastric acidity is reduced.

Adverse effects include nausea, headache, diarrhoea, constipation and rash but are uncommon. Omeprazole inhibits the 2C family of the cytochrome P450 system, decreasing the metabolism of warfarin, diazepam, carbamazepine and phenytoin, and enhancing the action of these drugs (but inhibition is less than with cimetidine).

Concern has arisen that long-term use of powerful antisecretory drugs may increase the risk of gastric neoplasia. Differing mechanisms have been proposed. When acid secretion is suppressed, gastrin is released as a normal homeostatic response. Gastrin stimulates growth of the gastric epithelium, including the enterochromaffin cells which could transform into carcinoid tumours; some rats developed these tumours after prolonged exposure to high doses of omeprazole. Furthermore, prolonged hypochlorhy-dria favours colonisation of the stomach by bacteria, which have the potential to convert ingested nitrates into carcinogenic nitrosamines. Surveillance studies to date have not provided evidence that this is a real hazard, and it is certainly unlikely with short-term use, e.g. up to 8 weeks.

Other theoretical concerns relate to reduced absorption of vitamin B12 and increased susceptibility to gastrointestinal infections as a result of prolonged hypochlorhydria. There is as yet no real evidence for these being a clinical problem.

Proton pump inhibitors are widely used and possible adverse effects from very long term exposure, e.g. resistant symptoms from gastro-oesophageal reflux disease, are not yet known.

Antimuscarinic drugs, e.g. pirenzepine, formerly widely used to suppress acid secretion, are now obsolete.

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Constipation Prescription

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