Calcium-Sandoz Forte

Pharmacodynamics. Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion through specific blockade of proton pumps in 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. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients become symptom-free within 2 weeks. Treatment with pantoprazole, as with other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and thereby increases gastrin secretion in proportion to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distally to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral and intravenous administration. Fasting gastrin levels increase during treatment with pantoprazole. During short-term treatment, 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 is observed (similar to adenomatoid hyperplasia). However, according to studies conducted to date, the formation of neuroendocrine tumour precursor cells (atypical hyperplasia) or gastric neuroendocrine tumours, which were observed in animal studies, has not been observed 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. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic investigations for neuroendocrine tumours. Available published data suggest that proton pump inhibitor therapy should be discontinued within 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 following a single oral dose of 40 mg. Peak serum concentrations of approximately 2–3 µg/mL are reached on average 2.5 hours after administration; concentrations remain constant after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Over the dose range of 10 to 80 mg, pantoprazole plasma pharmacokinetics remain 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 peak serum concentration, and therefore does not affect 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 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 the clearance is 0.1 L/h/kg. A few cases of delayed elimination have been observed. Due to the specific binding of pantoprazole to the proton pumps of parietal cells, the half-life does not correlate with the considerably longer duration of action (inhibition of acid secretion). The majority of pantoprazole metabolites are excreted renally (approximately 80%); the remainder is excreted in the 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 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-fold higher in poor metabolisers than in subjects with functionally active CYP2C19 enzyme (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 accumulation does not occur. 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 peak serum concentration increases only slightly — by a factor of 1.5 compared to healthy volunteers. Elderly patients. The slight increase in AUC and Cmax in elderly volunteers compared with younger volunteers is also not clinically relevant.