Chapter 30 The physiologic basis of diuretic drug action and synergism

Despite wide variations in dietary NaCl intake, homeostatic mechanisms insure that renal NaCl excretion matches intake, at steady state. This does not imply, however, that extracellular fluid volume is maintained within narrow limits. Unlike blood pressure, when dietary NaCl intake changes, extracellar fluid volume varies significantly even in normal individuals. Cardiac, liver, or renal disease can perturb the relation between NaCl intake and extracellular fluid volume and lead to symptomatic edema. Although diuretic drugs remain the mainstays in treating edematous patients, all major classes of diuretic drugs in use today were developed between 1950 and 1970. These drugs were developed without knowledge of specific ion transport, pathways, but experimental work during the past 15 years has shown that each major class of diuretic inhibits a specific ion transport protein in the kidney. These transport proteins have been characterized physiologically and the mechanisms by which each diuretic drug inhibits ion transport have been defined. Most recently, isoforms of each class of diuretic-sensitive Na transport pathway have been cloned. Treatment with diuretics leads to adaptive changes in nephron structure and function. These adaptations can limit the effectiveness of diuretic drugs used on a chronic basis. Maneuvers aimed at blocking these adaptive processes are effective approaches, to patients who become resistant to diuresis. Armed with knowledge of the physiologic basis of diuretic action and the mechanisms responsible for diuretic adaptation, even the most diuretic resistant patient can usually be treated successfully. Insights into the molecular basis of ion transport regulation should provide additional insights into mechanisms of edema formation and should provide more direct approaches to the treatment of edema.