Proton Pump Inhibitors

ECL cell activation mechanisms

3 main mechanisms

Vagal stimulation → ACh→ M1 maChR activation _> increase in histamine

gastrin release → cholecystokinin B (CCK-B) receptor activation → increased histamine

D-cell activation → SST → SST-2 receptor activation → decreased histamine

Erosive esophagitis

A condition where the lining of the esophagus becomes inflamed

Symptoms: difficulty swallowing, pain, bleeding

Persistent inflammation of the esophageal tissue. Also results in thinning over time

Suppression of stomach acid levels can contribute to healing of the esophageal lining

Irreversible inhibition of parietal cell proton pumps

Parietal cell proton pumps (H+/K+ ATPases) are responsible for the increase in gastric acidity

A drug that can selectively and irreversibly inhibit these H+/K+ATPases would allow symptom relief for extended periods

Irreversible inhibition can only be reversed through the expression of new H+/K+ ATPases, so short-term drug exposure can cause long-term effect

PPI design challenges

H+/K+ ATPases are not unique to the stomach; renal medulla also has them (important for potassium reabsorption)

H+/K+ ATPases are structurally similar to Na+/K+ ATPases and Ca2+ ATPases found in the heart and nerves, which may also be affected by PPIs

Successful PPIs must be able to

Survive the stomach conditions

Penetrate the membranes to reach its destination

Remain at the target tissue once delivered

General structure of PPIs

Several critical properties for success:

Acid trapping

Ability to cross the stomach membrane

Conversion into irreversible suicide inhibitors

PPI activation: entry into the gastric cannula

PPI activation: warhead activation

Acid trapping

pH of the stomach causes protonation of the molecule that causes it to be able to stay at its site once it makes it there - basically traps it in the gastric cannula

This does not happen in the renal medulla or other sites

PPI activation: irreversible inhibition

Enteric coating in PPIs

EC: a polymer barrier applied to oral medication. To prevent it from dissolving in the gastric environment(Can be used to bypass the harsh acidity of the gastric environment to prevent degredation)

Enteric coating considerations

Since coated molecules are absorbed at the intestines, onset is typically delayed by 2-3h (compare with H2RAs and antacids)

Food delays PPI absorption,so taking these drugs 30-60min before a meal allows maximal absorption and optimal inhibition → adherence issues

Crushing or chewing will destroy the protection provided by coating →must be taken whole

PPIs with alternative delivery mechanisms were also developed to address these shortcomings → will cover in the next lecture

Timoprazole

The first PPI, developed in 1975

Selective and irreversible inhibitor of parietal cell H+/K+. ATPases

Despite its short half-life, timoprazole was able to provide extended relief (1-2 days) in clinical studies

Acted as a goitrogen (interfered with thyroid fxn) due to benzimidazole functional group through thyroid peroxidase inhibition - never made it FDA approval