Physiology, p. 459
Introduction to Diuretics, p. 462 How Diuretics Work, p. 462
Adverse Impact on Extracellular Fluid, p. 462 Classification of Diuretics, p. 462
Loop Diuretics, p. 462 Furosemide, p. 462
Other Loop Diuretics, p. 464
Thiazides and Related Diuretics, p. 464 Hydrochlorothiazide, p. 464
Other Thiazide-Type Diuretics, p. 465 Potassium-Sparing Diuretics, p. 465
Spironolactone, p. 466 Triamterene, p. 466 Amiloride, p. 467
Mannitol: An Osmotic Diuretic, p. 467 Key Points, p. 468
Summary of Major Nursing Implications, p. 468
portion of Henle’s loop is located in the renal cortex and the lower end of the loop descends toward the renal medulla.
Without this orientation, the kidney could not produce con- centrated urine.
In addition to the nephrons, the collecting ducts (the tubules into which the nephrons pour their contents) play a critical role in kidney function. The final segment of the distal convoluted tubule (4b) plus the collecting duct into which it empties (5) can be considered a single functional unit: the distal nephron.
Physiology
Overview of Kidney Functions
The kidney serves three basic functions: (1) cleansing of extracellular fluid (ECF) and maintenance of ECF volume and composition; (2) maintenance of acid-base balance; and (3) excretion of metabolic wastes and foreign substances (e.g., drugs, toxins). Of the three, maintenance of ECF volume and composition is the one that diuretics affect most.
The Three Basic Renal Processes
Effects of the kidney on ECF are the net result of three basic processes: (1) filtration, (2) reabsorption, and (3) active secre- tion. To cleanse the entire ECF, a huge volume of plasma must be filtered. Furthermore, to maintain homeostasis, practically everything that has been filtered must be reabsorbed—leaving behind only a small volume of urine for excretion.
Filtration. Filtration occurs at the glomerulus and is the first step in urine formation. Virtually all small molecules (electrolytes, amino acids, glucose, drugs, metabolic wastes) that are present in plasma undergo filtration. In contrast, cells and large molecules (lipids, proteins) remain behind in the blood. The most prevalent constituents of the filtrate are sodium ions and chloride ions. Bicarbonate ions and potassium ions are also present, but in smaller amounts.
The filtration capacity of the kidney is very large. Each minute the kidney produces 125 mL of filtrate, which adds up to 180 L/day. Since the total volume of ECF is only 12.5 L, the kidneys can process the equivalent of all the ECF in the body every 100 minutes. Hence, the ECF undergoes complete cleansing about 14 times each day.
Be aware that filtration is a nonselective process and there- fore cannot regulate the composition of urine. Reabsorption and secretion—processes that display a significant degree of selectivity—are the primary determinants of what the urine ultimately contains. Of the two, reabsorption is by far the more important.
Diuretics are drugs that increase the output of urine. These agents have two major applications: (1) treatment of hyperten- sion and (2) mobilization of edematous fluid associated with heart failure, cirrhosis, or kidney disease. In addition, because of their ability to maintain urine flow, diuretics are used to prevent renal failure.
REVIEW OF RENAL ANATOMY AND PHYSIOLOGY
Understanding the diuretic drugs requires a basic knowledge of the anatomy and physiology of the kidney. Therefore, let’s review these topics before discussing the diuretics themselves.
Anatomy
The basic functional unit of the kidney is the nephron. As indicated in Fig. 41.1, the nephron has four functionally distinct regions: (1) the glomerulus, (2) the proximal convoluted tubule, (3) the loop of Henle, and (4a, 4b) the distal convoluted tubule.
All nephrons are oriented within the kidney such that the upper
filtrate, reabsorption of these ions is of greatest interest. As we discuss reabsorption, numeric values are given for the percentage of solute reabsorbed at specific sites along the nephron. Bear in mind that these values are only approximate. Fig. 41.2 depicts the sites of sodium and chloride reabsorption, indicating the amount of reabsorption that occurs at each site.
Proximal Convoluted Tubule. The proximal convoluted tubule (PCT) has a high reabsorptive capacity. A large fraction (about 65%) of filtered sodium and chloride is reabsorbed at the PCT. In addition, essentially all of the bicarbonate and potassium in the filtrate is reabsorbed here. As sodium, chloride, and other solutes are actively reabsorbed, water follows pas- sively. Since solutes and water are reabsorbed to an equal extent, the tubular urine remains isotonic (300 mOsm/L). By the time the filtrate leaves the PCT, sodium and chloride are the only solutes that remain in significant amounts.
Loop of Henle. The descending limb of the loop of Henle is freely permeable to water. Hence, as tubular urine moves down the loop and passes through the hypertonic environment of the renal medulla, water is drawn from the loop into the interstitial space. This process decreases the volume of the tubular urine and causes the urine to become concentrated (tonicity increases to about 1200 mOsm/L).
Within the thick segment of the ascending limb of the loop of Henle, about 20% of filtered sodium and chloride is Reabsorption. More than 99% of the water, electrolytes,
and nutrients that are filtered at the glomerulus undergo reabsorption. This conserves valuable constituents of the filtrate while allowing wastes to undergo excretion. Reabsorption of solutes (e.g., electrolytes, amino acids, glucose) takes place by way of active transport. Water then follows passively along the osmotic gradient created by solute reuptake. Specific sites along the nephron at which reabsorption takes place are dis- cussed later in this chapter. Diuretics work primarily by interfering with reabsorption.
Active Tubular Secretion. The kidney has two major kinds of “pumps” for active secretion. These pumps transport compounds from the plasma into the lumen of the nephron. One pump transports organic acids and the other transports organic bases. Together, these pumps can promote the excretion of a wide assortment of molecules, including metabolic wastes, drugs, and toxins. The pumps for active secretion are located in the proximal convoluted tubule.
Processes of Reabsorption That Occur at Specific Sites Along the Nephron
Because most diuretics act by disrupting solute reabsorption, to understand the diuretics, we must first understand the major processes by which nephrons reabsorb filtered solutes. Because sodium and chloride ions are the predominant solutes in the
2 1
4a
4b
3 Collecting 5
duct
Fig. 41.1 ■ Schematic representation of a nephron and collecting duct.
SPIRONOLACTONE, TRIAMTERENE Thick segment
ascending limb of Henle’s loop
Late distal convoluted tubule and collecting duct (distal nephron) Early distal
convoluted tubule Proximal
convoluted tubule
Fig. 41.2 ■ Schematic diagram of a nephron showing sites of sodium absorption and diuretic action.
The percentages indicate how much of the filtered sodium and chloride are reabsorbed at each site.
potassium excretion—can be viewed as an exchange mechanism.
This exchange is shown in Fig. 41.2. Aldosterone promotes sodium-potassium exchange by stimulating cells of the distal nephron to synthesize more of the pumps responsible for sodium and potassium transport.
reabsorbed (see Fig. 41.2). Since, unlike the descending limb, the ascending limb is not permeable to water, water must remain in the loop as reabsorption of sodium and chloride takes place.
This process causes the tonicity of the tubular urine to return to that of the original filtrate (300 mOsm/L).
Distal Convoluted Tubule (Early Segment). About 10% of filtered sodium and chloride is reabsorbed in the early segment of the distal convoluted tubule. Water follows passively.
Distal Nephron: Late Distal Convoluted Tubule and Collecting Duct. The distal nephron is the site of two important processes. The first involves exchange of sodium for potas- sium and is under the influence of aldosterone. The second determines the final concentration of the urine and is regulated by antidiuretic hormone (ADH). Although sodium-potassium exchange is discussed in more detail, we will not continue discussion of ADH, as it has little to do with the actions of diuretics.
Sodium-Potassium Exchange. Aldosterone, the principal mineralocorticoid of the adrenal cortex, stimulates reabsorp- tion of sodium from the distal nephron. At the same time, aldosterone causes potassium to be secreted. Although not directly coupled, these two processes—sodium retention and
Prototype Drugs
DIURETICS Loop Diuretics
Furosemide
Thiazide Diuretics Hydrochlorothiazide
Potassium-Sparing Diuretics Spironolactone
Triamterene
these drugs are employed primarily to lower intraocular pressure (IOP) and not to increase urine production. Conse- quently, the carbonic anhydrase inhibitors are discussed in Chapter 104.