Peptisolv IV Mechanism of Action

Pharmacotherapeutic Group: Proton pump inhibitors.
Pharmacology: Pharmacodynamics: Mechanism of action: Omeprazole is a racemic mixture of two active enantiomers that reduces gastric acid with a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cells. It has rapid action on acid secretion and reversibly inhibits gastric acid secretion with once-daily dosage.
Omeprazole is a weak base; it rapidly concentrates in the acidic media in the parietal cell where it is transformed to its active form to inhibit H+, K+-ATPase-acid pump enzyme which is the final step of gastric acid production. This effect on the final step of gastric acid production is dose-dependent and thus, irrespective of the stimulus, both basal and stimulated acid secretion are inhibited.
All pharmacodynamic effects observed can be explained by the effects of omeprazole on acid secretion.
Effect on gastric acid secretion: Intravenous omeprazole produces a dose-dependent gastric acid inhibition in humans. In order to rapidly achieve similar gastric acidity reduction to the one achieved by repeated oral dosing with 20 mg intravenously, a first dose of 40 mg is recommended. Both I.V. injection and I.V. infusion result in a rapid decrease in gastric acidity and approximately 90% decrease within 24 hours.
Inhibition of acid secretion is related to the area under the plasma concentration time curve (AUC), not with the actual plasma concentration of omeprazole.
No tachyphylaxis was observed during treatment with omeprazole.
Effect on Helicobacter pylori: Helicobacter pylori is associated with peptic ulcer disease, including gastric and intestinal ulcers. H. pylori is a primary factor forthe development of gastritis. H. pylori, together with gastric acid are major factors for the development of peptic ulcer disease. H. pylori is also a primary factor for the development of atrophic gastritis related with an increased risk of gastric cancer.
Omeprazole and antimicrobial agents provide H. pylori eradication, rapid symptomatic improvement, high rates of mucosal healing, and long-term improvement in peptic ulcer disease, which reduces complications, including gastrointestinal bleeding and need for anti-secretory treatments.
Other effects related to acid inhibition: Gastric glandular cysts may occur with increased frequency during long-term treatment. Such changes are physiological and occur as a result of inhibition of acid secretion; they appear to be benign and reversible. Decreased gastric acidity due to any reason, including proton pump inhibitors, causes an increase in the number of bacteria normally present in the gastrointestinal system. Treatment with proton pump inhibitors may slightly increase the risk of gastrointestinal infections with Salmonella and Campylobacter and potentially Clostridium difficile in hospitalized patients.
During treatment with anti-secretory medical products, serum gastrin is increased as a response to reduced acid secretion. Chromogranin A (CgA) also increases due to reduced gastric acidity. Increased CgA levels may interfere with investigations for neuroendocrine tumors. In order to avoid this, omeprazole treatment should be withheld 5 days before CgA measurements. In case CgA and gastrin levels do not return to normal within 5 days, measurements should be repeated after 14 days of omeprazole treatment interruption.
During long-term treatment with omeprazole, an increased count of chromaffin-like cells (ECL), possibly related to increased serum gastrin levels, was observed in some patients (children and adults). The findings were considered to be of no clinical relevance.
Pharmacokinetics: Distribution: The apparent volume of distribution in healthy subjects is approximately 0.3 L/kg body weight. Omeprazole is 97% bound to plasma proteins.
Biotransformation: Omeprazole is completely metabolized by the cytochrome P450 (CYP) system. The major part of the metabolism is dependent on polymorphically expressed specific isoform CYP2C19, which is responsible for the formation of the major metabolite hydroxyomeprazole in plasma. The remaining part is dependent on the other specific isoform CYP3A4, responsible for the formation of omeprazole sulphone. As a result of high affinity of omeprazole to CYP2C19, there is potential for competitive inhibition and metabolic drug-drug interaction between omeprazole and other CYP2C19 substrates. However, due to the low affinity of omeprazole to CYP3A4, there is no potential to inhibit the metabolism of other CYP3A4 substrates. Additionally, omeprazole has no inhibition effect on the main CYP enzymes.
Elimination: Total plasma clearance following a single dose is 30-40 L/hour. Plasma elimination half-life of omeprazole is shorter than one hour after both single and repeated once-daily oral dosing. Omeprazole is eliminated between doses. Approximately 80% of an intravenously administered dose is eliminated in the urine as metabolites, and the remainder is eliminated in feces mainly by bile secretion.
The area under the plasma-time curve (AUC) for omeprazole increases by repeated administrations, probably as a result of decreased systemic clearance due to CYP2C19 enzyme inhibition caused by omeprazole and/or its metabolites (e.g. sulphone).
None of the metabolites was found to have any effect on gastric acid secretion.
Patient characteristics: Renal impairment: Omeprazole pharmacokinetics, including systemic bioavailability and elimination rate, remain unchanged in patients with renal function impairment.
Hepatic impairment: AUC is increased in patients with impaired liver functions, however, once-daily oral dosing of omeprazole administration have not caused any accumulation.
Elderly: Metabolism rate of omeprazole is slightly reduced in the elderly (aged 75-79 years).
Children: There is limited experience with I.V. use in children.
Poor metabolizers: Approximately 3% of the Caucasian population and 15-20% of the Asian population have functional CYP2C19 enzyme deficiency, and they are called the weak metabolizers. Omeprazole metabolism is probably catalyzed mainly by CYP3A4 in these subjects. After repeated once-daily 20 mg omeprazole administration, mean AUC was 5 to 10 times higher in weak metabolizers compared to those with functional CYP2C19 enzymes. Mean peak plasma concentrations were 3 to 5 times higher. These findings do not affect omeprazole pathology.