Coffea Tosta

Pharmacodynamics. Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits the secretion of hydrochloric acid in the stomach 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 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, 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 treatment. 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, 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 neuroendocrine tumour precursor cells (atypical hyperplasia) or neuroendocrine tumours of the stomach, which were observed in animal studies, has not been found in humans. Based on the results of animal studies, an effect of long-term (longer 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 decreased acid secretion. Additionally, due to reduced gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may affect the results of investigations for the diagnosis of neuroendocrine tumours. Available published data suggest that PPI therapy 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 after 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; the concentration remains at a constant level 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 for both oral and intravenous administration. The absolute bioavailability of the tablets has been established to be approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or the maximum serum concentration, and consequently does not affect bioavailability. Only the variability of the lag time is increased 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 metabolized almost exclusively in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulfate conjugation; other metabolic pathways include oxidation by CYP3A4. Elimination. The terminal elimination half-life is approximately 1 hour and the clearance is 0.1 L/h/kg. A few cases of delayed elimination were 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 (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 sulfate. The half-life of the main metabolite (approximately 1.5 hours) does not greatly exceed that of pantoprazole. Special patient populations. Poor metabolizers. Approximately 3% of the European population lacks functional CYP2C19 enzyme activity; these individuals are referred to as poor metabolizers. In such individuals, the metabolism of pantoprazole is probably mainly catalyzed by CYP3A4. After a single oral dose of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolizers than in subjects with functionally active CYP2C19 enzyme (extensive metabolizers). 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 dialysis patients). As in healthy subjects, the half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination is still rapid, and therefore no accumulation occurs. Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B) the half-life increases to 7–9 hours and the AUC increases 5- to 7-fold, the maximum serum concentration is only slightly increased—by a factor of 1.5—compared to healthy volunteers. Elderly patients. A slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is also not clinically relevant.