Antimonium Tartaricum

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 the parietal cells, where it inhibits the H⁺/K⁺-ATPase enzyme, thereby blocking the final step of hydrochloric acid production in the stomach. This 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 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 whether the drug is 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 double in most 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, the formation of neuroendocrine tumour precursor cells (atypical hyperplasia) or gastric neuroendocrine tumours, which were observed in animal studies, have not been reported in humans. Based on the results of animal studies, an effect of long-term pantoprazole treatment (exceeding one year) on thyroid endocrine parameters cannot be excluded. During treatment with antisecretory medicinal products, serum gastrin levels increase in response to the reduction in 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 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 treatment. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and peak plasma concentrations are achieved after a single oral dose of 40 mg. Peak serum concentration of approximately 2–3 µg/mL is reached on average 2.5 hours after administration; this concentration remains constant after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, pantoprazole pharmacokinetics in plasma remain linear for both oral and intravenous administration. The absolute bioavailability of the tablets is approximately 77%. Concomitant food intake does not affect the AUC (area under the concentration–time curve) or peak 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 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 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 the European population lacks functional CYP2C19 enzyme activity; they are referred to as poor metabolisers. In these individuals, pantoprazole metabolism is likely catalysed primarily 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 functional CYP2C19 activity (extensive metabolisers). The mean peak plasma concentration was increased by approximately 60%. These findings do not affect pantoprazole dosing. Renal impairment. No dose reduction is recommended when prescribing 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 remains 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 the AUC increases 5- to 7-fold, the peak serum concentration increases only slightly—approximately 1.5-fold compared to healthy volunteers. Elderly patients. A slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is also not clinically significant.