Chlorchinaldin

Pharmacodynamics. Mechanism of action.​​​‍​​‍​​​​‍​​‍‍ Pantoprazole is a substituted benzimidazole that inhibits the secretion of hydrochloric acid in the stomach by specifically blocking 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. This 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 reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distally to the cellular receptor level, 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 pantoprazole treatment. During 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. An excessive increase, however, occurs only in isolated cases. As a result, a mild 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 carcinoid precursor cells (atypical hyperplasia) or gastric neuroendocrine tumours, which were observed in animal studies, has not been found in humans. Based on the results of animal studies, an effect of long-term (more than one year) pantoprazole treatment on endocrine thyroid parameters cannot be excluded. During treatment with antisecretory medicinal products, serum gastrin levels increase in response to the decrease in acid secretion. In addition, chromogranin A (CgA) levels increase due to reduced 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 prior to CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated after PPI treatment. Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentrations are achieved even after 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; these values remain constant after repeated dosing. Pharmacokinetic characteristics do not change after single or repeated administration. In the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole are 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 maximum serum concentration and, consequently, 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 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 (inhibition of acid secretion). 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 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; they are referred to as poor metabolisers. In these individuals, pantoprazole metabolism is likely catalysed mainly 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 functional CYP2C19 activity (extensive metabolisers). Mean peak plasma concentration was 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 dialysis patients). As in healthy individuals, the half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialysable. Although the main metabolite has a moderately longer half-life (2–3 hours), elimination is nonetheless rapid and accumulation does not occur. Hepatic impairment. Although the half-life increases to 7–9 hours in patients with hepatic cirrhosis (Child-Pugh classes A and B) and AUC increases 5- to 7-fold, the maximum serum concentration is only slightly increased — approximately 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 of no clinical significance.