Pharmacology of PPIs
Pharmacology of proton pump inhibition:
PPIs work by inhibiting the H+/K+ ATPase (proton pump). Proton pumps are located in the pump storage areas (the tubulovesicles) of the parietal cell. When a stimulus for acid secretion occurs, the tubulovesicles are rearranged and become part of the acid producing area of the parietal cell (the secretory canaliculus). This process is sometimes called “turning the pumps on”.
In the resting state (or basal state) of the parietal cell it is commonly stated that the “pumps are off”. In reality, in the basal state there is always some proton pump activity (although it may be very, very little).
The primary stimulus for “turning the pumps on” is the change in pH in the stomach from acid to more alkaline. This usually happens when food is present. Gastrin and histamine are the primary chemical mediators for this change. As the pH in the stomach rises to greater than 3, gastrin is released from the G cells. Gastrin then causes the release of histamine from the ECL (EnteroChromaffin-Like) cells. Histamine binds to the histamine 2 receptor on the parietal cell and “turns the pumps on”. The whole process from a resting (basal) parietal cell to a fully stimulated parietal cell takes approximately 15 minutes.
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(To view an animation on the parietal cell and stomach acid, click Introduction to Acid Secretion: location and stimulation of the parietal cell. The textbox at the bottom of each page describes the process currently being shown. After reading, use the navigation in the upper right-hand corner to continue to the following step.) |
(Note: acetylcholine and gastrin can also directly stimulate the parietal cell by means of separate receptors and this is why H2 receptor blockers can only partially block acid production).
Other substances that “turn on the pumps” include:
- Caffeine
- Coffee (without caffeine)
- Aromatic amino acids
- Pentagastrin given by intravenous route
- Sodium bicarbonate
Note: Modern day antacids such as Magnesium hydroxide and Aluminum hydroxide were developed because they DO NOT TURN ON THE PUMPS. Therefore, they are desirable as antacids. Antacids that turn on the pumps are referred to as causing a “REBOUND ACID SECRETING EFFECT”. REBOUND EFFECT is simply another way to say, “the pumps are turning on”. Because of the REBOUND EFFECT, sodium bicarbonate fell out of favor as an antacid.
There are TWO REQUIREMENTS for proton pump inhibition:- A PPI is present in the bloodstream
(and hence the site of action - the parietal cell. - The Proton Pumps are “turned on”
(i.e. the proton pumps are relocated to the secretory canaliculus – see above)
The foremost authority on Proton Pump Pharmacology is a text book written by George Sachs and Irvin Modlin. In fact, there are several textbooks and numerous papers that these authors have written about proton pump inhibition.
Click any drug in the list below to view an animation depicting its effect on the parietal cell and proton pump.
- AcipHex®
- Generic Omeprazole Delayed-release Capsule
- Nexium®
- Prevacid Capsule®
- Prevacid Delayed-release Suspension®
- Prevacid Solutab®
- Prilosec®
- Protonix®
- Zegerid™
Each animation will take you through the major steps of the PPI at work:
- drug is administered
- drug enters circulation
- proton pump inhibition begins
- blood concentration level of the drug reaches maximum
- proton pump inhibition declines
- parietal cells return to normal activity
- drug is no longer detectable in the bloodstream
Navigate through each animation using the timeline towards the bottom of each page.
Please continue to visit our site for updates on the animations as they become available.
For more information on the graphs used in the previous animations, see Citations.