Proton pump inhibitors (PPIs) are activated through protonation in the acidic environment of the parietal cell's secretory canaliculus.
Here's a breakdown of the activation process:
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Diffusion into Parietal Cells: PPIs, in their inactive form, enter parietal cells by diffusing across the cell membrane.
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Concentration in the Secretory Canaliculus: PPIs preferentially accumulate in the acidic environment of the secretory canaliculus of the parietal cell. This area has a very low pH due to the active pumping of protons (H+) by the H+/K+-ATPase (the proton pump).
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Protonation and Activation: The acidic environment (low pH) in the secretory canaliculus causes the PPI molecule to become protonated. This protonation triggers a structural rearrangement of the PPI molecule, converting it into its active form, a tetracyclic sulfonamide.
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Irreversible Binding: The active form of the PPI then covalently binds to the H+/K+-ATPase enzyme (the proton pump), specifically to cysteine residues. This binding is essentially irreversible, inhibiting the pump's activity and thus reducing gastric acid secretion. The pump needs to be replaced to restore acid secretion.
In summary, PPIs require an acidic environment to become activated and bind irreversibly to the proton pump. This localized activation ensures that the drug primarily inhibits acid production in the stomach.
