Diuretics

CHAPTER 41


Diuretics


Diuretics are drugs that increase the output of urine. These agents have two major applications: (1) treatment of hypertension 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 Figure 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 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 concentrated urine.


image
Figure 41–1  Schematic representation of a nephron and collecting duct.

In addition to the nephrons, the collecting ducts (the tubules into which the nephrons pour their contents) play a critical role in kidney function. As suggested by Figure 41–1, 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




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 secretion. In order to cleanse the entire ECF, a huge volume of plasma must be filtered. Furthermore, in order 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 therefore 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.





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 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. Figure 41–2 depicts the sites of sodium and chloride reabsorption, indicating the amount of reabsorption that occurs at each site.


image
Figure 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 is reabsorbed at each site.


Proximal convoluted tubule.

The proximal convoluted tubule (PCT) has a high reabsorptive capacity. As indicated in Figure 41–2, 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 passively. 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 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 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 potassium and is under the influence of aldosterone. The second determines the final concentration of the urine and is regulated by antidiuretic hormone (ADH).



Sodium-potassium exchange.


Aldosterone, the principal mineralocorticoid of the adrenal cortex, stimulates reabsorption 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 potassium excretion—can be viewed as an exchange mechanism. This exchange is shown schematically in Figure 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.









Regulation of urine concentration by ADH.


Although of great physiologic significance, ADH has little to do with the actions of diuretics. Hence, discussion of this physiologically important topic is presented in small type.


ADH acts on the collecting duct to regulate conservation of water. To understand the effects of ADH, we need to know four facts:



By rendering the collecting duct permeable to water, ADH allows water to be drawn from the duct as it passes through the hypertonic renal medulla. Because of this water reabsorption, urine that entered the duct in a relatively dilute state becomes concentrated and reduced in volume.


In the absence of ADH, water cannot be reabsorbed in the collecting duct. As a result, large volumes of dilute urine are produced. The clinical syndrome resulting from ADH deficiency is known as diabetes insipidus.




Introduction to diuretics


How diuretics work


Most diuretics share the same basic mechanism of action: blockade of sodium and chloride reabsorption. By blocking the reabsorption of these prominent solutes, diuretics create osmotic pressure within the nephron that prevents the passive reabsorption of water. Hence, diuretics cause water and solutes to be retained within the nephron, and thereby promote the excretion of both.


The increase in urine flow that a diuretic produces is directly related to the amount of sodium and chloride reabsorption that it blocks. Accordingly, drugs that block solute reabsorption to the greatest degree produce the most profound diuresis. Since the amount of solute in the nephron becomes progressively smaller as filtrate flows from the proximal tubule to the collecting duct, drugs that act early in the nephron have the opportunity to block the greatest amount of solute reabsorption. As a result, these agents produce the greatest diuresis. Conversely, since most of the filtered solute has already been reabsorbed by the time the filtrate reaches the distal parts of the nephron, diuretics that act at distal sites have very little reabsorption available to block. Consequently, such agents produce relatively scant diuresis.


It is instructive to look at the quantitative relationship between blockade of solute reabsorption and production of diuresis. Recall that the kidneys produce 180 L of filtrate a day, practically all of which is normally reabsorbed. With filtrate production at this volume, a diuretic will increase daily urine output by 1.8 L for each 1% of solute reabsorption that is blocked. A 3% blockade of solute reabsorption will produce 5.4 L of urine a day—a rate of fluid loss that would reduce body weight by 12 pounds in 24 hours. Clearly, with only a small blockade of reabsorption, diuretics can produce a profound effect on the fluid and electrolyte composition of the body.




Classification of diuretics


There are four major categories of diuretic drugs: (1) high-ceiling (loop) diuretics (eg, furosemide); (2) thiazide diuretics (eg, hydrochlorothiazide); (3) osmotic diuretics (eg, mannitol); and (4) potassium-sparing diuretics. The last group, the potassium-sparing agents, can be subdivided into aldosterone antagonists (eg, spironolactone) and nonaldosterone antagonists (eg, triamterene).


In addition to the four major categories of diuretics, there is a fifth group: the carbonic anhydrase inhibitors. Although the carbonic anhydrase inhibitors are classified as diuretics, these drugs are employed primarily to lower intraocular pressure (IOP) and not to increase urine production. Consequently, the carbonic anhydrase inhibitors are discussed in Chapter 104 (Drugs for the Eye) rather than here.



High-ceiling (loop) diuretics


The high-ceiling agents are the most effective diuretics available. These drugs produce more loss of fluid and electrolytes than any other diuretics. Because their site of action is in the loop of Henle, the high-ceiling agents are also known as loop diuretics.



Furosemide


Furosemide [Lasix] is the most frequently prescribed loop diuretic and will serve as our prototype for the group.



Mechanism of action

Furosemide acts in the thick segment of the ascending limb of Henle’s loop to block reabsorption of sodium and chloride (see Fig. 41–2). By blocking solute reabsorption, furosemide prevents passive reabsorption of water. Since a substantial amount (20%) of filtered NaCl is normally reabsorbed in the loop of Henle, interference with reabsorption here can produce profound diuresis.




Therapeutic uses

Furosemide is a powerful drug that is generally reserved for situations that require rapid or massive mobilization of fluid. This drug should be avoided when less efficacious diuretics (thiazides) will suffice. Conditions that justify use of furosemide include (1) pulmonary edema associated with congestive heart failure (CHF); (2) edema of hepatic, cardiac, or renal origin that has been unresponsive to less efficacious diuretics; and (3) hypertension that cannot be controlled with other diuretics. Furosemide is especially useful in patients with severe renal impairment, since, unlike the thiazides (see below), the drug can promote diuresis even when renal blood flow and glomerular filtration rate (GFR) are low. If treatment with furosemide alone is insufficient, a thiazide diuretic may be added to the regimen. There is no benefit to combining furosemide with another high-ceiling agent.



Adverse effects



Hypotension.

Furosemide can cause a substantial drop in blood pressure. At least two mechanisms are involved: (1) loss of volume and (2) relaxation of venous smooth muscle, which reduces venous return to the heart. Signs of hypotension include dizziness, lightheadedness, and fainting. If blood pressure falls precipitously, furosemide should be discontinued. Because of the risk of hypotension, blood pressure should be monitored routinely.


Outpatients should be taught to monitor their blood pressure and instructed to notify the prescriber if it drops substantially. Also, patients should be informed about symptoms of postural hypotension (dizziness, lightheadedness) and advised to sit or lie down if these occur. Patients should be taught that postural hypotension can be minimized by rising slowly.




Ototoxicity.

Rarely, loop diuretics cause hearing impairment. With furosemide, deafness is transient. With ethacrynic acid (another loop diuretic), irreversible hearing loss may occur. The ability to impair hearing is unique to the high-ceiling agents. Diuretics in other classes are not ototoxic. Because of the risk of hearing loss, caution is needed when high-ceiling diuretics are used in combination with other ototoxic drugs (eg, aminoglycoside antibiotics).













Drug interactions


Digoxin.

Digoxin is used for heart failure (see Chapter 48) and cardiac dysrhythmias (see Chapter 49). In the presence of low potassium, the risk of serious digoxin-induced toxicity (ventricular dysrhythmias) is greatly increased. Since high-ceiling diuretics promote potassium loss, use of these drugs in combination with digoxin can increase the dysrhythmia risk. This interaction is unfortunate in that most patients who take digoxin for heart failure must also take a diuretic as well. To reduce the risk of toxicity, potassium levels should be monitored routinely, and, when indicated, potassium supplements or a potassium-sparing diuretic should be given.




Potassium-sparing diuretics.

The potassium-sparing diuretics (eg, spironolactone, triamterene) can help counterbalance the potassium-wasting effects of furosemide, thereby reducing the risk of hypokalemia.








Lithium.


Lithium is used to treat bipolar disorder (see Chapter 33). In patients with low sodium, excretion of lithium is reduced. Hence, by lowering sodium levels, furosemide can cause lithium to accumulate to toxic levels. Accordingly, lithium levels should be monitored, and, if they climb too high, lithium dosage should be reduced.






Other high-ceiling diuretics


In addition to furosemide, three other high-ceiling agents are available: ethacrynic acid [Edecrin], torsemide [Demadex], and bumetanide [Burineximage, generic only in United States.]. All three are much like furosemide. They all promote diuresis by inhibiting sodium and chloride reabsorption in the thick ascending limb of the loop of Henle. All are approved for edema caused by heart failure, chronic renal disease, and cirrhosis, but only torsemide, like furosemide, is also approved for hypertension. All can cause ototoxicity, hypovolemia, hypotension, hypokalemia, hyperuricemia, hyperglycemia, and disruption of lipid metabolism, specifically, reduction of HDL cholesterol and elevation of LDL cholesterol and triglycerides. Lastly, they all share the same drug interactions: Their effects can be blunted by NSAIDs, they can intensify ototoxicity caused by aminoglycosides, they can increase cardiotoxicity caused by digoxin, and they can cause lithium to accumulate to toxic levels. Routes, dosages, and time courses are summarized in Table 41–1.

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Jul 24, 2016 | Posted by in NURSING | Comments Off on Diuretics

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