Diuretic drugs. Progress in clinical pharmacology

Oral diuretics are amongst the most widely used drugs in clinical practice today. Their discovery close on thirty years ago remains a major milestone in therapeutic progress. Though originally designed for treating heart failure, diuretics are more commonly prescribed, worldwide, in hypertension than for relief of oedema. Since the introduction of chlorothiazide, diuretic development has passed through a series of distinct stages. The thiazide era was followed by the 'high-ceiling' diuretics, the antikaliuretics and, more recently, polyvalent agents that cause both saluresis and uricosuria. Alongside these synthetic achievements, major advances have occurred in the knowledge of nephron function and ion transport mechanisms. These have acted as stimulus to the design of novel categories of diuretics. The practising clinician thus has a wide range of available diuretics to choose from. The most appropriate choice of an agent aimed at the relief of symptoms with minimal adverse effects requires an understanding of where and how diuretics act within their primary target organ, the kidney. Whereas various procedures, ranging from micropuncture to the study of brush border membrane vesicles, have been utilised experimentally, investigation of the mode and sites of action of diuretics in man has largely depended on application of clearance methodology. Refinements in analytical chemistry have encouraged study of the pharmacokinetic and metabolic fate of diuretics. Taken together, available evidence shows that most diuretics exert their saluretic action from the intraluminal aspect of the renal tubules. The time-course of drug delivery, as well as total quantity of drug transported into the lumen determine the cumulative drug response. Exceptions are muzolimine and the aldosterone antagonists which act at the peritubular membrane. Distinctive stereospecific effects on luminal tubular ion transport occur with indacrinone and etozoline. The clinical use of diuretics often involves concurrent administration with other drugs. The mechanisms involved in a number of the resulting pharmacodynamic and pharmacokinetic interactions have considerable relevance in patient management. Notable examples of these interactions are the blunting of diuretic action by non-steroidal anti-inflammatory agents and the diuretic-induced diminution in the renal clearance of lithium salts.