The overall goal of this project is to assess and probe potential mechanisms of the decreased response to furosemide that occurs in a variety of clinical settings such as congestive heart failure, liver disease, and renal disease. Resistance to diuretics could occur through disease-induced changes in disposition of the drug including altered quantity or time course of absorption after oral administration or changed disposition after intravenous administration. Alternatively, or in addition, disease-induced changes in response to amounts of drug delivered to the site of action could occur. We propose to assess in patients with diseases in which resistance to diuretics occurs whether changes in pharmacokinetics and/or in pharmacodynamics occur. If so, we propose to attempt correlations of changes in kinetics with indices of disease severity to allow speculation as to possible mechanisms of altered handling and to allow predictions in other patients which might facilitate therapeutic strategy. We also propose studies to attempt to elucidate possible mechanisms of altered pharmacodynamics which, in turn, may provide insights into the pathogenesis of solute retention in these disease states.
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