Proton pump inhibitors
ESOMEPRAZOLE/OMEPRAZOLE, LANSOPRAZOLE, PANTOPRAZOLE, RABEPRAZOLE
"Despite claims to the contrary, all proton pump inhibitors have equivalent efficacy at comparable doses"
Goodman and Gilman, 11 ed. |
Pharmacokinetics
- OMEPRAZOLE is a racemic mixture; ESOMEPRAZOLE is exclusively the active S-isomer
- the R-isomer is converted to the active S-isomer by CYP2C19
- differences in activity of this enzyme alter the effectiveness of OMEPRAZOLE in some patients ("poor metabolizers"), giving ESOMEPRAZOLE a therapeutic advantage
- the proportion of poor metabolizers varies in populations (e.g., only 10% of caucasians but 70% of South Pacific Islanders are poor metabolizers)
- PPIs are acid-labile prodrugs that are administered in acid-resistant formulations (either with an enteric coating, or combined with sodium bicarbonate) - the enteric coatings dissolve in the intestinal lumen where the prodrugs are absorbed and circulate throughout the body
- the prodrugs preferentially diffuse into acidified compartments (i.e., the parietal cell canaliculi) where they are protonated, concentrated >1000-fold and converted to the active forms which bind IRREVERSIBLY to H+/K+ ATPase
- timing of administration is critical:
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PPIs must be ADMINISTERED in the fasting state, when gastric motility is low
- bioavailability is decreased approximately 50% by food because larger amplitude movements crush the protective coatings, exposing the prodrugs to the stomach acid (which is in high concentration) and causing them to be inactivated
- PPIs only inhibit active pumps
- however, in a fasting state, only 10% of pumps are actively secreting acid and susceptible to inhibition à administer PPIs ~ 1 hour before a meal, so that peak serum concentrations coincide with maximal pump activity
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PPIs must be ADMINISTERED in the fasting state, when gastric motility is low
- short t½, however, at least 18 hours are required for synthesis of new pump molecules à significant acid inhibition lasts approx. 24 hours
→ once daily dosing- the long duration of effect means that differences in pharmacokinetic profiles among PPIs are functionally insignificant (with the exception of the poor metabolizers)
- full acid inhibition is seen only after 3-4 days of daily medication (similarly, takes 3-4 days for acid secretion to return to normal when drug is stopped)
- higher loading dose is used initially, then reduced after symptoms have been controlled
- undergo first pass metabolism (CYP2C19 and CYP3A4); negligible renal clearance
- ESOMEPRAZOLE, LANSOPRAZOLE and PANTOPRAZOLE are available IV for treatment of stress-induced ulcers, particularly in the ICU
- must be given as continuous IV or repeated bolus injections when patients are fasting (only 10% of pumps are active and can be blocked by the drug)