Arsenicum Album

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. The 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 thereby increases gastrin secretion proportionally to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme at a site distal to the cellular receptor, it can inhibit hydrochloric acid secretion independently 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 generally do not exceed the upper limit of normal. 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 gastric neuroendocrine tumours, which were observed in animal studies, has not been seen in humans. Based on animal study results, an effect of long-term (greater 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 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 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. The peak serum concentration of approximately 2–3 µg/mL is reached on average 2.5 hours after administration; the concentration remains at a steady level after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, pantoprazole pharmacokinetics in plasma remain linear after both oral and intravenous administration. The absolute bioavailability of tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration–time curve) or peak 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 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 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 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 have a functional deficiency of the CYP2C19 enzyme 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-fold greater in poor metabolisers than in subjects with functionally active CYP2C19 (extensive metabolisers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect the dosing of pantoprazole. Renal impairment. No dose reduction recommendations apply 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 longer half-life (2–3 hours), elimination is still rapid; therefore, accumulation does not occur. Hepatic impairment. Although the half-life increases to 7–9 hours and the AUC increases 5- to 7-fold in patients with hepatic cirrhosis (Child-Pugh class A and B), the peak serum concentration increases only slightly — approximately 1.5-fold compared with healthy volunteers. Elderly patients. A slight increase in AUC and Cmax in elderly volunteers compared with younger volunteers is not clinically significant.