Cantharis

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 become symptom-free within 2 weeks. Administration of pantoprazole, as with other proton pump inhibitors (PPIs) and H2-receptor inhibitors, reduces gastric acidity and thereby increases gastrin secretion proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds to 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 identical whether the drug is administered orally or intravenously. During pantoprazole treatment, fasting gastrin levels increase. 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 consequence, 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 neuroendocrine tumours of the stomach, which were observed in animal studies, have not been found in humans. Based on the results of animal studies, an effect of long-term (more than one year) pantoprazole treatment on thyroid gland endocrine parameters cannot be excluded. During treatment with antisecretory medicinal products, serum gastrin levels increase in response to the decrease in acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may affect the results of investigations for neuroendocrine tumours. Available published data suggest that PPI treatment should be discontinued within 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 maximum 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 remains at a constant level after repeated doses. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, plasma pharmacokinetics of pantoprazole remain linear both after 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 accordingly 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 with subsequent sulphate 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 parietal cell proton pumps, the elimination half-life does not correlate with the much longer duration of action (acid secretion inhibition). The major portion of pantoprazole metabolites is excreted renally (approximately 80%); the remainder is 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 the half-life of pantoprazole. Special patient populations. Poor metabolisers. Approximately 3% of Europeans have a functional deficiency of the CYP2C19 enzyme; they are called poor metabolisers. In these individuals, pantoprazole metabolism is probably 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 a functionally active CYP2C19 enzyme (extensive metabolisers). 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 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, so accumulation does not occur. Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh class A and B) the half-life increases to 7–9 hours and the AUC increases 5–7 fold, the maximum serum concentration increases only slightly — by 1.5 times 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.