Omeprazole - How It Works
Clinical pharmacology details from the US FDA-approved label: how Omeprazole works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H + /K + ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H + /K + ATPase enzyme system at the secretory surface of the gastric parietal cell.
Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production.
This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
12.2 Pharmacodynamics Antisecretory Activity After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour, with the maximum effect occurring within two hours.
Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours.
The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H + /K + ATPase enzyme.
When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days.
The inhibitory effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days.
Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of omeprazole in healthy subjects and patients are shown below.
The “max” value represents determinations at a time of maximum effect (2 to 6 hours after dosing), while “min” values are those 24 hours after the last dose of omeprazole.
Table 5: Range of Mean Values from Multiple Studies of the Mean Antisecretory Effects of Omeprazole After Multiple Daily Dosing Omeprazole 20 mg Omeprazole 40 mg Parameter Max Min Max Min % Decrease in Basal Acid Output 78 1 58-80 94 1 80-93 % Decrease in Peak Acid Output 79 1 50-59 88 1 62-68 % Decrease in 24–hr Intragastric Acidity 80-97 92-94 1.
Single Studies Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24-hour intragastric acidity in some patients.
Serum Gastrin Effects In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion.
No further increase in serum gastrin occurred with continued treatment.
In comparison with histamine H 2 -receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs.
1.1 to 1.8 fold increase).
Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.
Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels.
The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see W arnings and Precautions ] .
Enterochromaffin-like (ECL) Cell Effects Human gastric biopsy specimens have been obtained from more than 3000 patients (both children and adults) treated with omeprazole in long-term clinical trials.
Pharmacokinetics
12.3 Pharmacokinetics Omeprazole is a time-dependent inhibitor of CYP2C19, resulting in autoinhibition and nonlinear pharmacokinetics. The systemic exposure increases in a more than dose proportional manner after multiple oral doses of omeprazole. Compared to the first dose, the systemic exposure (C max and AUC 0-24h ) at steady state following once a day dosing increased by 61% and 62%, respectively, compared to after the first dose for the 20 mg dose of Omeprazole Delayed-Release Capsules and increased by 118% and 175%, respectively, for the 40 mg dose of Omeprazole Delayed-Release Capsules. Absorption Omeprazole Delayed-Release Capsules contain an enteric-coated microtablet formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the microtablets leave the stomach. Absorption is rapid, with peak plasma concentrations of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30 to 40% at doses of 20 to 40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500 to 600 mL/min. The bioavailability of omeprazole increas