Proton Pump Inhibitors
Proton pump inhibitors are used to reduce acid production in the stomach, either to treat gastro-oesophageal reflux or as part of treatment for gastric or duodenal ulceration or eradication of H.pylori. They were originally launched in the 1980’s and have a long history of use. They are generally regarded as safe but they do confer some risks, particularly for vulnerable individuals (see side effects later on). Proton pump inhibitors include drugs like omeprazole, lansoprazole, pantoprazole and esomeprazole. They all have similar efficacy although invariably manufacturers will often claim their product has superiority few head to head trials between PPIs have been undertaken.
Proton pump inhibitors all work by blocking the “proton pump,” a membrane proton that transports hydrogen ions (acid) across cell membranes. This is the final common pathway by which acid is produced by the cells lining the stomach (parietal cells) and secreted into the stomach. Proton pump inhibitors therefore significantly reduce the quantity of acid in the stomach. They are effective for approximately 85 to 95% of patients with gastro-oesophageal reflux depending on the dose used.
This class of drugs has been widely prescribed for the management of acid related disease. This includes oesophageal reflux, oesophagitis, resistant peptic ulcer disease and gastrinoma. The indications for PPI use are listed in the table below as can be seen some indications are widely agreed others are rather more debatable. PPIs provide effective and sustained reduction in gastric acid production and are effective for between 80 to 95% of patients with acid reflux depending on how the disease is defined and the dose administered. There are now an array of proton pump inhibitors available. They work by blocking the excretion of hydrogen ions (acid) via the hydrogen/potassium adenosine triphosphate enzyme, which acts as a trans mebrane pump from the inside to the outside of the parietal cell within the stomach.
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Indications for PPI
Gastroesophageal reflux disease
Barrett’s Oesophagus
Treatment and recurrent prophylaxis of peptic ulcers
Eradication of Helicobacter pylori
Pathologic hypersecretory conditions (e.g. Zollinger–Ellison syndrome)
Histological proven diagnosis of gastritis
Prevention of medication-induced ulcers;
NSAIDs in patients >65 years old
NSAIDs and corticosteroid use
NSAIDs and warfarin / coumadin use
NSAIDs and patient history of ulcer/ GI bleeding
Aspirin and corticosteroid
Aspirin and warfarin/coumadin
Aspirin and NSAID
Indications rated as uncertain
Dyspepsia
Oesophageal varices
Ulcer prophylaxis with clopidogrel and low dose aspirin
Patient underwent upper gastrointestinal endoscopy and biopsy, result outstanding at discharge
History of gastritis, no endoscopy, no further information
Omeprazole, the first proton pump inhibitor to be developed is 100% metabolised in liver and 80% of the metabolic products are then excreted in the urine, a further 20% are excreted in bile which is found in the stools. Other proton pump inhibitors generally have similar metabolism. Rabeprazole is not activated until it reaches the acid environment of the stomach/ parietal cell.
Proton pump inhibitors are powerful drugs and have a range of potential side effects on the gastrointestinal system, risk of infection and nutritional status. The commonest side effect is change in bowel habit, which may be a shift towards loose stool or constipation. Bloating and abdominal pain may also arise either as a direct result of the medication or consequent upon ensuing changes in the microbiome or small intestinal bacterial overgrowth. Nausea, vomiting and headache may also occur. The commonest nutritional deficiency associated with proton pump inhibitor usage is that of hypomagnesaemia (low blood magnesium). Low magnesium levels are relatively uncommon in patients on PPIs who has otherwise normal diets and gut function. Low magnesium is much commoner in those patients taking proton pump inhibitors who also have other gastro-intestinal pathology or a history of chronic disease or alcohol misuse. B12deficiency is also associated with PPI use.
The commonest side effect is loose stools (1-2% of patients develop this) but bloating, nausea and headache are also not uncommon. There is also an increased risk of acquiring infectious diarrhoea. Some patients, particularly those with other risk for maldigestion or malabsorption, are at risk of developing problems with magnesium absorption. Low magnesium levels are associated with osteoporosis, but there are far stronger association with both smoking and alcohol use which are also associated with risk of reflux disease for which proton pump inhibitors are used as a treatment. In the event that patients on proton pump inhibitors are admitted to intensive care units they have a significantly increased risk of developing healthcare associated pneumonia.
There are also other associations between proton pump inhibitors, dementia cardiovascular risk and stroke disease. It is not clear whether these associations are causative (In other words the proton pump inhibitors cause the disease) or whether it relates to the fact that people who smoke, drink and are sedentary or obese have a greater likelihood of developing both reflux and the other conditions that are associated with these habits.