Pharmacology of Proton Pump Inhibitors (PPIs)

PPIs are the drugs used to treat gastric hyperacidity, peptic ulcers, and GERD.

Mechanism of Action of Proton Pump Inhibitors

Proton Pump Inhibitors (PPIs) selectively and irreversibly block the gastric proton pump (H⁺/K⁺-ATPase) on the stomach's parietal cells. This inhibits stomach acid release.

Proton Pump Structure

Gastric parietal cells contain the transmembrane protein gastric proton pump. Its alpha and beta subunits initiate gastric acid synthesis.

Acid Secretion Process

Histamine, gastrin, and acetylcholine trigger the parietal cells' proton pump to discharge H⁺ into the stomach lumen. Exchanging potassium ions (K⁺) from the parietal cells with protons from the stomach's acidic environment generates protons.

PPI Binding

Proton Pump Inhibitors are weak bases that enter the circulation and passively diffuse into parietal cells. PPIs are protonated and activated in parietal cells' secretory canaliculi's acidic environment.

Covalent Binding

PPIs attach to the alpha subunit's cysteine residues following activation. Irreversible covalent binding prevents the proton pump from actively providing stomach protons.

Inhibition of Acid Secretion

PPIs lower stomach acid by irreversively blocking the proton pump. Thus, intragastric pH rises and stomach acidity falls.

PPIs lower stomach acid and speed up healing for acid-related disorders such peptic ulcers and GERD.

PPIs simply control acid secretion and may not treat H. pylori infection or NSAID-induced damage, which may require extra treatment.

Pharmacological Actions of Proton Pump Inhibitors

Inhibition of Gastric Acid Secretion

The main action of PPIs is the inhibition of gastric acid secretion by targeting the proton pump (H⁺/K⁺-ATPase) in the parietal cells of the stomach.

Acid Suppression

PPIs lower stomach acidity and raise stomach pH. This decrease in gastric acid alleviates peptic ulcer, GERD, and other acid-related symptoms.

Peptic Ulcer with Esophagitis Healing

PPIs cure stomach and duodenal peptic ulcers by lowering gastric acid output. Gastric acid reflux causes erosive esophagitis, and contributes to its repair.

Symptomatic Relief of GERD

PPIs reduce acid reflux into the oesophagus and relieve GERD symptoms. This reduces heartburn, regurgitation, and other GERD symptoms.

Prevention of NSAID-Induced Ulcers

PPIs prevent NSAID-induced stomach and duodenal ulcers. Reduced acid output and increased stomach pH protect the gastric mucosa.

Therapeutic Uses of Proton Pump Inhibitors

Gastroesophageal Reflux Disease (GERD)

GERD, a chronic illness that causes heartburn, regurgitation, and chest discomfort, is often treated with PPIs. GERD symptoms are reduced with PPIs.

Peptic Ulcer Disease

PPIs cure peptic ulcers, open sores in the stomach or upper small intestine. PPIs reduce stomach acid and cure ulcers by repairing damaged tissue.

Helicobacter Pylori Infection

H. pylori infection, which causes peptic ulcers, is typically treated with PPIs. PPIs and antibiotics kill H. pylori and cure ulcers.

Zollinger-Ellison Syndrome

PPIs are used in the management of Zollinger-Ellison syndrome, a rare condition characterized by the overproduction of gastric acid. PPIs help reduce the excessive acid production and control the symptoms associated with this syndrome, such as abdominal pain and diarrhea.

Non-Ulcer Dyspepsia

Non-ulcer dyspepsia is recurrent stomach pain without a structural cause. It can be treated with PPIs. PPIs reduce stomach acid, alleviating discomfort.

Prevention of Nonsteroidal Anti-Inflammatory Drug (NSAID) Induced Ulcers

Aspirin and ibuprofen irritate the stomach and cause ulcers. Long-term NSAID users may receive PPIs to lower the risk of ulcers.

Adverse Effects of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) might have some adverse effects if misused.

Gastrointestinal Symptoms

PPIs cause diarrhoea, constipation, stomach discomfort, bloating, and nausea. Some people have minor, temporary effects.

Increased Risk of Infections

PPIs lower stomach acid, which might weaken the immune system. Long-term PPI usage increases the risk of gastrointestinal infections such C. difficile and community-acquired pneumonia.

Nutrient Deficiencies

Gastric acid helps absorb vitamin B12, magnesium, calcium, and iron. PPIs may deplete these minerals, affecting bone health, anaemia, and other metabolic activities.

Increased Fracture Risk

Long-term PPI usage may raise the risk of osteoporotic hip, wrist, and spine fractures. This association's mechanism is still being studied.

Kidney Complications

PPI users may develop acute interstitial nephritis, inflammation in kidneys. Swelling, bloody urine, fever, and rash are symptoms. These symptoms require immediate medical intervention.

Increased Risk of Certain Conditions

Llong-term PPI usage may cause Chronic renal disease, dementia, cardiovascular events, and stomach cancer. However, further study is needed to demonstrate causation.

Drug Interactions of Proton Pump Inhibitors

PPIs can alter the absorption, metabolism, or efficacy of other drugs. PPIs interact with these drugs.

Clopidogrel

Clopidogrel is used as antiplatelet drug. The antiplatelet action of Clopidogrel may be reduced by PPIs, especially omeprazole and esomeprazole. PPIs may block clopidogrel activation, reducing its antiplatelet effects. Clopidogrel patients may use ranitidine instead of PPIs.

Anticoagulants

When taken with warfarin or direct oral anticoagulants such apixaban or rivaroxaban, PPIs may increase bleeding risk. Monitor coagulation parameters and alter anticoagulant dose as needed.

Methotrexate

PPIs may raise methotrexate levels. Methotrexate is employed in treatment of cancer and autoimmune disease. It may exacerbate methotrexate toxicity. PPIs should be monitored for methotrexate levels and dosage changes.

Atazanavir and Other Antiretroviral Drugs

In HIV therapy the action of atazanavir is reduced by PPIs. PPIs reduce the effectiveness of atazanavir. Therefore the concurrent administration of PPIs and atazanavir is prohibited.

Other Drugs

Ketoconazole, itraconazole, and iron supplements may interact with PPIs. PPIs may decrease drug absorption and efficacy. These drugs should be taken many hours after PPIs.

Precautions and Contraindications of Proton Pump Inhibitors

Hypersensitivity

PPIs should not be taken by anyone who are allergic to them or their ingredients. PPIs can cause skin rashes to life-threatening anaphylaxis.

Pregnancy and Breastfeeding

PPIs should only be used during pregnancy or breastfeeding under medical supervision.

Liver Dysfunction

PPIs are primarily metabolized in the liver. PPI metabolism and disposal may be hindered in severe liver impairment. Adjustments or new drugs may be needed.

Osteoporosis and Fracture Risk

Long term therapy of Rabeprazole increases the risk of osteoporotic fractures, particularly in the elderly patients.

Deficiencies in vitamins and minerals

Long term use of Omeprazole may cause vitamin and mineral deficiencies, including vitamin B12, magnesium, calcium, and iron.

C. Difficile Infection

PPIs increase the risk of C. difficile infection, which causes severe diarrhoea. If PPI usage causes chronic diarrhoea, it should be diagnosed and treated immediately.

Interference with Diagnostic Tests

PPIs can affect stomach cancer and H. pylori testing. Before these tests, notify healthcare providers about PPI usage, since temporary withdrawal may be needed for reliable findings.