Ezoprole Mechanism of Action

Pharmacology: Pharmacodynamics: Esomeprazole is a proton pump inhibitor (PPI) that belongs to the substituted benzimidazole derivative class of antisecretory compounds. Esomeprazole is the S-isomer of omeprazole. It suppresses gastric acid secretion by specific inhibition of the (H⁺, K⁺)-ATPase enzyme system at the secretory surface of the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion.
Pharmacokinetics: Esomeprazole is acid labile and is therefore given as enteric-coated to prevent deterioration in the stomach. Esomeprazole is rapidly absorbed after oral administration and peak plasma concentrations occur within 1 to 2 hours. The bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once daily administration. For the 20 mg, the corresponding values are 50 and 68% respectively. Food delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.
The apparent volume of distribution at steady state is approximately 0.22 L/kg body weight. Esomeprazole is 97% bound to plasma proteins.
Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) isoenzyme CYP2C19 to form hydroxy and desmethyl metabolites, which have no effect on gastric acid secretion. The remainder is metabolized by CYP3A4 to form esomeprazole sulfone. There is a decrease in first-pass metabolism and systemic clearance with repeated dosage caused by an inhibition of CYP2C19 isoenzyme. However, there is no accumulation during once daily use.
The total plasma clearance of esomeprazole is approximately 17 L/h after a single dose and 9 L/h after repeated administration. The plasma elimination half-life is approximately 1.3 hours. Almost 80% of an oral dose is excreted as metabolites in the urine, and the remainder is found in the feces.
Special Populations: Poor Metabolizers: Approximately 3% of the Caucasian population and 15% to 20% of Asian population lack a functional CYP2C19 isoenzyme and are called poor metabolizers. In such individuals, the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. At steady state, the ratio of the area under the plasma concentration-time curve (AUC) of esomeprazole in poor metabolizers to the AUC in the rest of the population (extensive metabolizers) is approximately 2:1.
Elderly: The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age). However, increased sensitivity of some older patients cannot be ruled out.
Hepatic Impairment: The metabolism of esomeprazole is decreased in patients with severe hepatic impairment resulting in a 2 to 3 times higher AUC.