Amflee

Pharmacodynamics. Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits the secretion of hydrochloric acid in the stomach 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 enzyme H⁺/K⁺-ATPase, thereby blocking the final step of hydrochloric acid production in the stomach. The inhibition is dose-dependent and applies to both basal and stimulated acid secretion. Most patients achieve 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 proportionally to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme at a site distal to the cell receptor, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is administered orally or intravenously. Fasting gastrin levels increase during treatment with pantoprazole. With short-term use, they do not exceed the upper limit of normal in most cases. During long-term treatment, gastrin levels double in most cases. Excessive increases occur only in isolated cases. As a result, in a small number of cases during long-term treatment, a mild to moderate increase in specific endocrine (ECL) cells in the stomach has been observed (similar to adenomatoid hyperplasia). However, according to studies conducted to date, the formation of neuroendocrine tumour precursor cells (atypical hyperplasia) or neuroendocrine tumours of the stomach, which were observed in animal studies, has not been found in humans. Based on results from animal studies, the effect of long-term (longer than one year) treatment with pantoprazole on endocrine parameters of the thyroid gland cannot be excluded. During treatment with antisecretory medicinal products, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to reduced gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with investigations for neuroendocrine tumours. Available published data suggest that PPI therapy should be discontinued between 5 days and 2 weeks prior to CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated following PPI therapy. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and peak plasma concentrations are achieved after a single oral dose of 40 mg. The maximum serum concentration of approximately 2–3 µg/mL is reached on average 2.5 hours after administration; concentration levels remain constant after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole remain linear for both oral and intravenous administration. The absolute bioavailability of the tablets has been established at approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or the maximum serum concentration, and consequently does not affect bioavailability. Only the variability of the lag time increases with concomitant food intake. Distribution. Serum protein binding of pantoprazole is approximately 98%. The volume of distribution is approximately 0.15 L/kg. Biotransformation. The substance is metabolised almost exclusively in the liver. The main metabolic pathway is demethylation by CYP2C19, followed by sulphate conjugation; other metabolic pathways include oxidation by CYP3A4. Elimination. The terminal 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 the proton pumps of parietal cells, the 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 faeces. The main metabolite in both serum and urine is desmethylpantoprazole conjugated with sulphate. The half-life of the main metabolite (approximately 1.5 hours) is not much longer than that of pantoprazole. Special patient populations. Poor metabolisers. Approximately 3% of the European population lack functional CYP2C19 enzyme activity and are referred to as poor metabolisers. In these individuals, pantoprazole metabolism is likely mainly catalysed 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 metabolisers than in subjects with functionally active CYP2C19 (extensive metabolisers). The mean peak plasma concentration was increased by approximately 60%. These findings have no implications for the dosing of pantoprazole. Renal impairment. No dose reduction is recommended when pantoprazole is administered 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 dialysed. 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 in patients with hepatic cirrhosis (Child-Pugh classes A and B) the half-life increases to 7–9 hours and AUC increases 5- to 7-fold, the maximum serum concentration increases only slightly — 1.5-fold compared to that in healthy volunteers. Elderly patients. A slight increase in AUC and Cmax in elderly volunteers compared with younger volunteers is also not clinically relevant.