Agnus Castus

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 of 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 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 in proportion to the reduction in acidity. The increase in gastrin secretion is reversible. Because pantoprazole binds the enzyme at a site 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 drug is administered orally or intravenously. Fasting gastrin levels increase during pantoprazole therapy. With short-term use, these levels generally do not exceed the upper limit of normal. During long-term treatment, gastrin levels typically double. Excessive increases occur only in isolated cases. Consequently, 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 have been observed in animal studies, has not been seen in humans. Based on results from animal studies, the 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 reduced acid secretion. In addition, chromogranin A (CgA) levels increase due to decreased gastric acidity. 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 before CgA measurements. This allows CgA levels to return to the normal range, as they may be falsely elevated following PPI treatment. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and peak plasma concentrations are reached after a single oral dose of 40 mg. The peak serum concentration of approximately 2–3 µg/mL is reached on average 2.5 hours after administration; concentrations 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 after 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 the maximum serum concentration and, consequently, 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 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 considerably 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 Europeans lack functional CYP2C19 enzyme activity and 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 individuals with functionally active CYP2C19 (extensive metabolisers). Mean peak plasma concentration increased by approximately 60%. These findings do not affect 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 dialysable. 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 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), the maximum serum concentration increases only slightly — approximately 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 significant.