Chapter 25

### INTRODUCTION

What engineer, wishing to regulate the composition of the internal environment of the body on which the function of every bone, gland, muscle, and nerve depends, would devise a scheme that operated by throwing the whole thing out 16 times a day and rely on grabbing from it, as it fell to earth, only those precious elements which he wanted to keep?

Homer Smith, From Fish to Philosopher

As the philosophizing physiologist, Homer Smith, noted, the kidney filters the extra cellular fluid volume across the renal glomeruli an average of 16 times a day, and the renal nephrons precisely regulate the fluid volume of the body and its electrolyte content via processes of secretion and reabsorption. Disease states such as hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis may disrupt this balance. Diuretics increase the rate of urine flow and Na+ excretion and are used to adjust the volume and/or composition of body fluids in these disorders. Precise regulation of body fluid osmolality is also essential. It is controlled by a finely tuned homeostatic mechanism that operates by adjusting both the rate of water intake and the rate of solute-free water excretion by the kidneys—that is, water balance. Abnormalities in this homeostatic system can result from genetic diseases, acquired diseases, or drugs and may cause serious and potentially life-threatening deviations in plasma osmolality.

This chapter first describes renal anatomy and physiology, then introduces diuretics with regard to chemistry, mechanism of action, site of action, effects on urinary composition, and effects on renal hemodynamics, and finally, integrates diuretic pharmacology with a discussion of mechanisms of edema formation and the role of diuretics in clinical medicine. Specific therapeutic applications of diuretics are presented in Chapters 27 (hypertension) and 28 (heart failure).

The second half of this chapter describes the physiological mechanisms that regulate plasma osmolality and factors that perturb those mechanisms, and examines pharmacological approaches for treating disorders of water balance.

### RENAL ANATOMY AND PHYSIOLOGY

The basic urine-forming unit of the kidney is the nephron, which consists of a filtering apparatus, the glomerulus, connected to a long tubular portion that reabsorbs and conditions the glomerular ultrafiltrate. Each human kidney is composed of ~1 million nephrons. The nomenclature for segments of the tubular portion of the nephron has become increasingly complex as renal physiologists have subdivided the nephron into shorter and shorter named segments. These subdivisions were based initially on the axial location of the segments but increasingly have been based on the morphology of the epithelial cells lining the various nephron segments. Figure 25–1 illustrates subdivisions of the nephron.

Glomerular Filtration. In the glomerular capillaries, a portion of plasma water is forced through a filter that has three basic components: the fenestrated capillary endothelial cells, a basement membrane lying just beneath the endothelial cells, and the filtration slit diaphragms formed by epithelial cells that cover the basement membrane ...

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