Sites of action of loop diuretics.

Isolated canine kidneys were perfused at a constant systolic pressure of 140 mm Hg with autologous blood. Infusion of maximally effective amounts of furosemide (F) increased the fractional excretion of Cl (FEcl) from 0.03 to 0.18. Parallel changes in FENa and FEH2O were observed and, at maximal response, urine/plasma osmolality was 0.91. Ethacrynic acid (EA) was then added to the infusion fluid and produced a further increase in FECl to 0.28. Urine/plasma osmolality returned to unity. When the order of administration of the two diuretics was reversed, the response to EA alone was greater than after F (from FECl 0.05 control to 0.30 after EA) and the urine became isosmotic (urine/plasma osmolality = 1.0). After F was added, FECl increased further to 0.39. K secretion induced by F or by EA was demonstrable in all experiments. These data indicate that: 1) EA is more effective than F; 2) both drugs can completely inhibit Cl- transport in the thick ascending limb; 3) EA is more effective than F in blocking NaCl transport at sites distal to the loop of Henle; and 4) the proximal tubule is a site of action of F and possibly of EA. Whether the two drugs act entirely on membranal transport systems or, in part, by modifying the production of release of intrarenal substances and/or by diverting blood from one region to another cannot be ascertained from this work.

Renal tubular handling of drugs.

The renal excretion of drugs is a vectorial quantity, the resultant of physiologic mechanisms that have directional orientation and magnitude. Magnitude is limited by a variety of extrarenal factors including plasma protein binding and the volume of the total body water. The contributions of the glomeruli and tubules to excretion varies with age. This fact has clinical relevance, especially in newborn children and older patients. Although protein binding reduces the amount of a drug that can be filtered, it usually does not alter the rate of proximal tubular secretion of charged organic molecules. Reabsorption of the filtered fluid from tubular lumens creates concentration gradients favoring the reabsorption of drugs, but the movement of drug molecules out of luminal fluid is hindered by the formation of polar drug metabolites in the liver. Although there are only a few examples in the literature, it is probable that many drugs are reabsorbed by a carrier-mediated process located in the proximal tubules. A major difference exists between the renal handling of chlormerodrin, a neutral mercurial, and of mersalyl, an acidic mercurial. Chlormerodrin is reabsorbed (as a complex with cysteine) by a carrier-mediated process; mersalyl is secreted by one of the organic anion transport systems.

Thiol adducts of ethacrynic acid: a correlation of the rate of liberation of ethacrynic acid with the onset and magnitude of the diuretic response.

It is thought that a derivative of ethacrynic acid (EA) must possess an intact alpha, beta-unsaturated ketone group in order to be capable of eliciting a diuretic response. The 2,3-dimercapto-1-propanol and the cysteine adducts of ethacrynic acid lack such a functional group and still have diuretic activity, especially the cysteine adduct. An in vitro study showed that various thiol adducts of EA liberate EA and the accompanying thiol at a rate that is primarily dependent on the nature of the functional groups present in the thiol portion of the adduct. When the thiol adducts of EA were injected into dogs, the cysteine and mercaptoethylamine hydrochloride adducts which rapidly release EA under specific in vitro conditions were as effective as EA in producing a diuretic response. The onset of action was also similar to that of EA. The thiosalicylic acid adduct of EA releases the accompanying thiol at an intermediate rate in vitro and was less effective than EA in a small dose (3.3 mumol/kg) and the peak response to it was slower to develop. Other adducts that release EA and the accompanying thiol slowly in vitro either produce a very weak response which takes considerable time to develop or are completely devoid of diuretic activity. Thus, the onset and magnitude of the diuretic response produced by various thiol adducts of EA (with the possible exception of the cysteine adduct) are governed primarily by the rate of in vivo release of EA.