Pharmacology of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of stomach acid production. They are among the most widely sold drugs in the world, and are generally considered safe. The following are examples of PPIs:

  1. Omeprazole (Prilosec)
  2. Lansoprazole (Prevacid)
  3. Dexlansoprazole (Dexilant)
  4. Esomeprazole (Nexium)
  5. Pantoprazole (Protonix)
  6. Rabeprazole (Aciphex)

Mechanism of Action

PPIs work by irreversibly blocking the hydrogen/potassium pump in the stomach lining. This pump is responsible for the final step in gastric acid production. The flowchart below illustrates this process:

proton pump inhibitors mechanism of action in peptic ulcer
#Mechanism of action of Proton Pump Inhibitors


After oral administration, PPIs are absorbed in the stomach, but food delays and reduces absorption. They are extensively metabolized in the liver by the cytochrome P450 system. The metabolites are excreted in urine and feces.

Absorption: PPIs are weak bases that are absorbed in the small intestine. They are lipophilic and are absorbed into the systemic circulation. The rate and extent of absorption are influenced by the formulation of the PPI and the presence of food. For example, omeprazole’s absorption is delayed and reduced by food, while pantoprazole’s absorption is not significantly affected.

Distribution: Once absorbed, PPIs are distributed throughout the body. They are highly protein-bound, primarily to plasma albumin. This high degree of protein binding may limit the distribution of PPIs into body tissues.

Metabolism: PPIs are extensively metabolized in the liver by the cytochrome P450 (CYP) system. Different PPIs are metabolized by different CYP isoenzymes. For example, omeprazole, esomeprazole, and lansoprazole are primarily metabolized by CYP2C19, while pantoprazole and rabeprazole are primarily metabolized by CYP2C19 and CYP3A4. Genetic polymorphisms in CYP2C19 can affect the metabolism of PPIs, leading to differences in plasma concentrations and clinical effects among individuals.

Excretion: The metabolites of PPIs are primarily excreted in the urine. A small amount may also be excreted in the feces. The elimination half-life of PPIs is typically 1-2 hours, but this can be prolonged in individuals with impaired liver function.

Their half-life is about 1-2 hours, but their effect lasts much longer due to the irreversible inhibition of the proton pumps.

Pharmacological Actions

PPIs suppress gastric acid secretion by inhibiting the gastric H+/K+ ATPase at the secretory surface of the gastric parietal cell. This effect leads to basal and stimulated acid secretion inhibition, thereby increasing gastric pH, reducing pepsin activity, and promoting mucosal healing.

Therapeutic Uses

PPIs are used in the treatment of conditions such as:

  • Gastroesophageal reflux disease (GERD)
  • Peptic ulcer disease (PUD)
  • Zollinger-Ellison syndrome
  • Prevention of stress ulcers
  • Alongside antibiotics for the eradication of Helicobacter pylori

Side Effects

Common side effects of PPIs include:

  • Headache
  • Nausea
  • Diarrhea
  • Abdominal pain
  • Fatigue
  • Dizziness

Long-term use can lead to serious side effects, including:

  • Vitamin B12 deficiency
  • Magnesium deficiency
  • Increased risk of bone fractures
  • Infections such as pneumonia and Clostridium difficile


PPIs are contraindicated in patients with known hypersensitivity to any formulation component. Caution should be exercised in patients with severe liver disease.

Drug Interactions

PPIs can interact with other drugs like:

  • Clopidogrel: PPIs can reduce the effectiveness of clopidogrel, a medication used to prevent heart attacks and strokes.
  • Methotrexate: PPIs can increase the levels of methotrexate, a medication used to treat cancer and autoimmune diseases.
  • Warfarin: PPIs can increase the risk of bleeding when used with warfarin, a blood thinner.

Always consult with a healthcare provider for a complete list of possible interactions and warnings.

Remember, while PPIs are generally considered safe, they should be used under the supervision of a healthcare provider and for the shortest duration necessary.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.


Here are some frequently asked questions (FAQs) about Proton Pump Inhibitors (PPIs):

  1. What is a PPI? Proton Pump Inhibitors (PPIs) are a type of medication that reduces the production of stomach acid. They are commonly used to treat conditions like gastroesophageal reflux disease (GERD) and stomach ulcers.
  2. How do PPIs work? PPIs work by irreversibly blocking the hydrogen/potassium pump in the stomach lining, which is responsible for the final step in gastric acid production.
  3. Are there any side effects of PPIs? While PPIs are generally considered safe, they can have side effects. Some potential side effects include headache, diarrhea, nausea, and abdominal pain. Long-term use of PPIs has been associated with an increased risk of fractures, pneumonia, and Clostridium difficile infections.
  4. Can PPIs be used for mild heartburn? While PPIs are effective for treating chronic stomach acid problems, they may not be necessary for mild, occasional heartburn. Over-the-counter antacids or H2 blockers may be sufficient for mild cases.
  5. Are there any concerns about long-term use of PPIs? Long-term use of PPIs can lead to potential issues such as reduced calcium absorption, which could lead to osteoporosis and increased fracture risk. There may also be an increased risk of pneumonia and Clostridium difficile infections.
  6. Can PPIs affect the absorption of other nutrients? There were initial concerns that PPIs could affect the absorption of iron and vitamin B12, but research has shown that if there is any effect, it’s mild.
  7. Are all PPIs the same? While all PPIs work similarly, there are differences in their chemical properties and how they are metabolized. Therefore, the choice of PPI may depend on individual patient factors and cost considerations.

Remember, it’s always important to discuss any concerns or questions you have about medications with your healthcare provider.

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