Antimonium Crudum

Pharmacodynamics. Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion by specifically blocking the proton pumps of parietal cells. Pantoprazole is converted to its active form in the acidic environment of parietal cells, where it inhibits the H⁺/K⁺-ATPase enzyme, thereby blocking the final step of hydrochloric acid production in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients experience symptom relief within 2 weeks. Administration of pantoprazole, as with other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and consequently increases gastrin secretion in proportion to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether administered orally or intravenously. Fasting gastrin levels increase during pantoprazole therapy. With short-term use, they do not exceed the upper limit of normal in most cases. During long-term treatment, gastrin levels generally double. Excessive increases occur only in isolated cases. As a consequence, a mild to moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) is observed in a small number of cases during long-term treatment. However, according to studies conducted to date, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal studies, has not been seen in humans. Based on the results of animal studies, an effect of long-term (more than one year) pantoprazole treatment on thyroid endocrine parameters cannot be excluded. During treatment with antisecretory medicinal products, serum gastrin levels increase in response to decreased acid secretion. In addition, chromogranin A (CgA) levels increase due to reduced gastric acidity. Elevated CgA levels may interfere with diagnostic investigations for neuroendocrine tumors. Available published data suggest that PPI therapy should be discontinued for a period of 5 days to 2 weeks prior to CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated following PPI treatment. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and peak plasma concentrations are achieved after a single oral dose of 40 mg. The mean peak serum concentration of approximately 2–3 µg/mL is reached approximately 2.5 hours after administration; the concentration remains at a constant level after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Over the dose range of 10 to 80 mg, plasma pharmacokinetics of pantoprazole are linear following both oral and intravenous administration. The absolute bioavailability of tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or peak serum concentration, and therefore bioavailability. Only the variability of the lag time increases with concomitant food intake. Distribution. Pantoprazole serum protein binding is approximately 98%. The volume of distribution is approximately 0.15 L/kg. Biotransformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation by CYP2C19 followed by sulfate conjugation; other metabolic pathways include oxidation by CYP3A4. Elimination. The terminal elimination half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. A few cases of delayed elimination have been noted. Due to the specific binding of pantoprazole to proton pumps of parietal cells, the elimination half-life does not correlate with the much longer duration of action (acid secretion inhibition). The majority of pantoprazole metabolites are excreted renally (approximately 80%), with the remainder excreted in feces. The main metabolite in both serum and urine is desmethylpantoprazole conjugated with sulfate. The half-life of the main metabolite (approximately 1.5 hours) is not much longer than that of pantoprazole. Special patient populations. Poor metabolizers. Approximately 3% of Europeans have a functional deficiency of CYP2C19 enzyme activity; they are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is probably catalyzed primarily by CYP3A4. After a single dose of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times greater in poor metabolizers than in subjects with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration was increased by approximately 60%. These findings have no implications for pantoprazole dosing. Renal impairment. No dose reduction is recommended when administering pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy subjects, the half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination is still rapid, and therefore no accumulation occurs. Hepatic impairment. Although the half-life increases to 7–9 hours and the AUC increases 5- to 7-fold in patients with hepatic cirrhosis (Child-Pugh classes A and B), the peak serum concentration increases only slightly—by 1.5-fold compared to that in healthy volunteers. Elderly patients. The slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is also not clinically significant.