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Extensive studies have been carried Post Date: Thu, 16 Oct 2008 17:20:30 +0000 Localization of Site of Drug Action. There is uniform agreement that most diuretics act directly on the kidney and, with few exceptions, on tubular rather than glomerular function. Extensive studies have been carried out to localize further the site of action to discrete segments of the nephron. Autor of the post: Undefined Despite this intense activity, it Post Date: Thu, 16 Oct 2008 17:06:51 +0000 A varietyof methods have been employed. These include the clearance technic, stop-flow analysis, micropuncture, histochemistry, enzyme assay, the direct determi-nation of the composition of renal tissue, in-vitro studies with kidney slices and isolated tubules, and, by inference, examination of related systems, partic-ularly frog skin and toad bladder preparations.Despite this intense activity, it is not possible to correlate all observations in a definitive manner. Autor of the post: Undefined Third, there may be important Post Date: Thu, 16 Oct 2008 16:51:23 +0000 Brief comment on some of the complexities is war-ranted. First, a drug does not necessarily act at the site at which its concentration is maximal Second, a drug may act on separate transport mechanisms at different sites—for example, the action of mercurials on the tubular secretion of organic acids proximally and on that of potassium distally. Third, there may be important species differences, most marked in the case of uricosuric agents but also observed with some diuretics. Autor of the post: Undefined This applies to many discrete Post Date: Thu, 16 Oct 2008 16:36:20 +0000 Fourth, although popularly simplified in terms of a single schematic nephron, the operation of the kidney is actually accomplished by millions of individual units that may respond differently both to physiological stress and to the action of diuretics. Fifth, modern concepts of renal function emphasize the architectural integrity of the nephron as an entire unit. This applies to many discrete functions, including solute reab-sorption, the operation of the countercurrent system, and the determinants of bidirectional transport, that is, secretion in one segment and reabsorption in another. Autor of the post: Undefined These secondary effects may Post Date: Thu, 16 Oct 2008 16:16:59 +0000 In the case of the countercurrent mecha-nism, for example, the magnitude of water reabsorp-tion from the collecting duct is determined primarily by solute reabsorption in the ascending limb. And, sixth, particularly in the case of the quantitative interpretation of sodium and water reabsorption, a drug action at one site may be accompanied by secondary and compensatory changes in transport at another segment. These secondary effects may be mediated by normal mechanisms, rather than by drug action at both sites. Autor of the post: Undefined " However, there is increasing evidence Post Date: Thu, 16 Oct 2008 16:00:57 +0000 Depending on the experi-mental technic, the compensatory changes may ob-scure the primary action. It has long been recognized that changes in solute reabsorption in one segment may influence tubular function at more distal sites that are "downstream." However, there is increasing evidence that the reverse may also be true. Autor of the post: Undefined Since sodium, the major solute Post Date: Thu, 16 Oct 2008 15:50:36 +0000 Distal events may influence more proximal transport. The mechanisms are both intrarenal and extrarenal in nature. Since sodium, the major solute of the tubular fluid, is reabsorbed throughout most portions of the nephron, it is quite possible that many drugs that inhibit its reabsorption act at more than a single site. Autor of the post: Undefined Many of the newer diuretics Post Date: Thu, 16 Oct 2008 15:31:46 +0000 The apparent localization of drug action to a partic-ular locus may in large part be determined by exper-imental conditions, as well as by quantitative differ-ences between the actions of the diuretic agent at different sites (see Goldberg, 1973; Suki et at, 1973).Extrarenal Sites of Drag Action. Many of the newer diuretics have proven to be useful in the investigation of electrolyte transport in organs other than the kidney, particularly under in-vitro condi-tions. Autor of the post: Undefined For many drugs, their predominantly Post Date: Thu, 16 Oct 2008 15:18:18 +0000 Not surprisingly, these studies have revealed fundamental mechanisms common to many tissues. However, these are not reviewed systematically inthis chapter unless the action at the extrarenal site occurs with reasonable dosages and is of sufficient magnitude to have clinical relevance. For many drugs, their predominantly renal site of action may be attributed to the high concentration of drug achieved within the kidney. Autor of the post: Undefined WATERMechanism of Water Diuresis Post Date: Thu, 16 Oct 2008 15:00:04 +0000 WATER AND OSMOTIC DIURETICSNormally the volume of urine is largely determined by the concentrations and types of solutes delivered to the renal tubule. Therefore, water and various electrolytes and nonelectrolytes can act as diuretic agents when given in excess.WATERMechanism of Water Diuresis. 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