When cumulative drug effect determines clinical response then schedule dependence should be expected. Schedule dependence occurs because of the nonlinear concentration-effect relationship and also requires that the action of the drug is rapidly reversible.
There are two situations when cumulative effect and clinical response may not be schedule dependent. If the doses do not reach concentrations above the EC50 then the concentration-effect relationship will be essentially linear and schedule dependence will not occur. The other case is for drugs, which bind irreversibly to the site of action. Proton pump inhibitors bind irreversibly (e.g., omeprazole) and would be expected to have the same cumulative effect on acid suppression irrespective of the dosing schedule in one day because the turnover and regeneration of new pump molecules takes several days.
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