Amflee

Pharmacodynamics. Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion through specific blockade of the proton pumps of parietal cells. Pantoprazole is converted to its active form in the acidic environment within parietal cells, where it inhibits the H⁺/K⁺-ATPase enzyme, thereby blocking the final step of hydrochloric acid production in the stomach. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients become symptom-free within 2 weeks. Administration of pantoprazole, as with other proton pump inhibitors (PPIs) and H₂-receptor antagonists, reduces gastric acidity and thereby increases gastrin secretion in proportion to the decrease in acidity. The increase in gastrin secretion is reversible. Because pantoprazole binds the enzyme distal to the cell receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the medicinal product is administered orally or intravenously. Fasting gastrin levels increase during treatment with pantoprazole. During short-term use, they do not exceed the upper limit of normal in the majority of cases. During long-term treatment, gastrin levels double in the majority of cases. Excessive increases occur only in isolated cases. As a result, a slight 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, formation of neuroendocrine tumour precursor cells (atypical hyperplasia) or gastric neuroendocrine tumours, as observed in animal studies, has not been found in humans. Based on the results of animal studies, the influence of long-term pantoprazole treatment (longer than one year) on endocrine thyroid parameters cannot be excluded. During treatment with antisecretory medicinal products, serum gastrin levels rise in response to decreased acid secretion. In addition, chromogranin A (CgA) levels increase due to decreased gastric acidity. 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 before CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated after PPI therapy. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentrations are achieved even after a single oral dose of 40 mg. Maximum serum concentrations of approximately 2–3 µg/mL are reached on average 2.5 hours after administration; concentrations remain at a steady level after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, pantoprazole plasma pharmacokinetics are linear following both oral and intravenous administration. The absolute bioavailability of the tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration–time curve) or maximum serum concentration, and therefore does not affect bioavailability. Only the variability of the lag time is increased 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 with subsequent 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 the 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%); the remainder is excreted in faeces. 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 metabolisers. Approximately 3% of Europeans lack functional CYP2C19 enzyme activity; they are referred to as poor metabolisers. In these individuals, pantoprazole metabolism is probably mainly catalysed by CYP3A4. After a single 40 mg dose of 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). Mean peak plasma concentration was increased by approximately 60%. These findings do not affect dosing recommendations for pantoprazole. 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 dialysed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination is still rapid, so accumulation does not occur. Hepatic impairment. Although the half-life increases to 7–9 hours and AUC increases 5- to 7-fold in patients with hepatic cirrhosis (Child-Pugh classes A and B), maximum serum concentration increases only slightly — by 1.5-fold compared with 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.