Resistance to diuretics: emphasis on a pharmacological perspective

Resistance to diuretics occurs frequently in clinical settings. Most attention to this phenomenon has been directed toward the pathophysiology of the disease state, with little focus on the pharmacology of the diuretics themselves. This review summarises the pathogenesis and emphasises the pharmacological determinants of response to diuretics, including absorption, delivery to the kidney, and response to amounts of diuretic reaching the site of action. In normal subjects, overall response to organic acid diuretics such as frusemide (furosemide) is determined by the total amount of drug delivered into the urine (reflecting amounts of drug reaching the intraluminal site of action), the time course of delivery, and the relationship between amounts of drug reaching the urine and response (the dynamics of response). The conditions of azotaemia, inhibition of synthesis of prostaglandins, and the oedematous disorders of congestive heart failure, cirrhotic liver disease and nephrotic syndrome are examined in the above context. In azotaemic subjects, delivery of organic acid diuretics to their intraluminal site of action is inhibited by accumulated endogenous organic acids which compete for transport into the nephron at the organic acid secretory site of the proximal tubule. Whether the dynamics of response are changed has not been investigated. During inhibition of synthesis of prostaglandins, and in the oedematous disorders, there appear to be no changes in handling of frusemide; i.e. bioavailability, total drug delivered into the urine and the time course of delivery are comparable with that in normal subjects unless concomitant renal dysfunction exists. Resistance in these conditions is therefore due to a change in the dynamics of response.