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WEBINAR REPLAY

Back to the tuture: A review of PPIs

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A vector of gastrointestinal bacteria and capsules

The launch of omeprazole in 1989 marked a significant breakthrough in gastroenterology, offering a new and more effective option for managing conditions caused by excess stomach acid.

PPIs, such as omeprazole, esomeprazole, and pantoprazole, work by targeting the proton pump (hydrogen-potassium adenosine triphosphatase) in the stomach’s parietal cells. This pump is responsible for secreting gastric acid when stimulated, typically after eating.

PPIs inhibit this enzyme, leading to reduced acid production and alleviating symptoms of acid-related diseases, allowing for healing of the oesophagus, stomach lining, and duodenum in conditions like GORD, peptic ulcers, and Zollinger-Ellison syndrome.

The primary mechanism of PPIs involves binding to the proton pump in the parietal cells, irreversibly inhibiting acid secretion. By doing so, they provide a prolonged effect, as acid production remains suppressed until new proton pumps are synthesised, which takes about 24-hours.

Despite their short half-life of one to two hours, PPIs offer sustained acid suppression, typically achieving a steady-state inhibition of ~66% after two to three days of regular dosing. This makes them especially effective in treating conditions where long-term acid suppression is required, such as GORD or Barrett’s oesophagus.

The efficacy of PPIs depends on their absorption and activation in the body. Once absorbed in the small intestine, PPIs accumulate in the acidic environment of the stomach’s parietal cells.

There, they are converted into their active form, which then binds to cysteine residues on the proton pump, blocking acid production. Because the synthesis of new proton pumps occurs more actively at night, PPIs are typically administered in the morning before breakfast to maximise their effectiveness.

Different PPIs vary in their pharmacokinetics and acid-suppressive capabilities. Rabeprazole, for instance, is known for its rapid onset of action, reaching near-maximal inhibition of acid secretion within five minutes of administration.

It is also less dependent on the cytochrome P450 2C19 enzyme for metabolism, making it less prone to drug interactions, particularly in patients who are also taking medications like clopidogrel. Lansoprazole has the highest bioavailability among orally administered PPIs, with peak plasma concentration occurring between 0.5 to 3.5 hours after administration.

Some PPIs are designed to provide better nocturnal acid suppression, addressing the limitations of once-daily dosing. Dual-release formulations are available to enhance acid suppression, particularly during nighttime, when acid reflux can be more problematic for some patients. Increasing the dose of a PPI does not significantly enhance its effect, but twice-daily dosing can result in around 80% inhibition of acid output.

While PPIs are generally safe and effective, they are best tailored to individual patient needs. Long-term use of PPIs is necessary for certain conditions, such as Barrett’s oesophagus or Zollinger-Ellison syndrome, where ongoing acid suppression is crucial.

However, many patients can transition to on-demand therapy after their condition improves. Physicians should carefully assess whether prolonged PPI use is necessary, as long-term use has been associated with potential risks such as nutrient deficiencies, kidney disease, and increased susceptibility to infections.

In summary, PPIs have transformed the management of acid-related diseases, offering effective, long-term acid suppression with relatively few side effects. With variations in potency, pharmacokinetics, and formulation, PPIs provide flexible treatment options for a wide range of acid-related conditions, ensuring optimal patient care when prescribed appropriately.

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