Diuretics increase the rate of urine volume output, as the name implies. Most diuretics also increase urinary excretion of solutes, especially sodium and chloride. In fact, most diuretics that are used clinically act by decreasing renal tubular sodium reabsorption, which causes natriuresis (increased sodium output), in turn causing diuresis (increased water output). That is, in most cases, increased water excretion occurs secondary to inhibition of tubular sodium reabsorption because sodium remaining in the tubules acts osmotically to decrease water reabsorption. Because renal tubular reabsorption of many solutes, such as potassium, chloride, magnesium, and calcium, is also influenced secondarily by sodium reabsorption, many diuretics raise the renal output of these solutes as well.

The most common clinical use of diuretics is to reduce extracellular fluid volume, especially in diseases associated with edema and hypertension. As discussed in Chapter 25, loss of sodium from the body mainly decreases extracellular fluid volume; therefore, diuretics are most often administered in clinical conditions in which extra cellular fluid volume is expanded.

Some diuretics can increase urine output more than 20fold within a few minutes after they are administered. However, the effect of most diuretics on renal output of salt and water subsides within a few days (Figure 1). This is due to activation of compensatory mechanisms initiated by decreased extracellular fluid volume. For example, a decrease in extracellular fluid volume may reduce arterial pressure and the glomerular filtration rate (GFR) and increase renin secretion and angiotensin II formation; all these responses together eventually override the chronic effects of the diuretic on urine output. Thus, in the steady state, urine output becomes equal to intake, but only after reductions in arterial pressure and extracellular fluid volume have occurred, relieving the hypertension or edema that prompted the use of diuretics in the first place.

Fig1. Sodium excretion and extracellular fluid volume during  diuretic administration. The immediate increase in sodium excretion  is accompanied by a decrease in extracellular fluid volume. If sodium  intake is held constant, compensatory mechanisms will eventually  return sodium excretion to equal sodium intake, thus re-establishing  sodium balance. 

The many diuretics available for clinical use have different mechanisms of action and, therefore, inhibit tubular reabsorption at different sites along the renal nephron. The general classes of diuretics, their mechanisms of action, and their tubular sites of action are shown in Table 1.

Table1. Classes of Diuretics, Their Mechanisms of Action, and Tubular Sites of Action

OSMOTIC DIURETICS DECREASE WATER REABSORPTION BY INCREASING THE OSMOTIC PRESSURE OF TUBULAR FLUID

Injection into the blood stream of substances that are not easily reabsorbed by the renal tubules, such as urea, mannitol, and sucrose, causes a marked increase in the con centration of osmotically active molecules in the tubules. The osmotic pressure of these solutes then reduces water reabsorption, flushing large amounts of tubular fluid into the urine.

Large volumes of urine are also formed in certain dis eases associated with excess solutes that fail to be reabsorbed from the tubular fluid. For example, when blood glucose concentration rises to high levels in diabetes mellitus, the increased filtered load of glucose into the tubules exceeds their capacity to reabsorb glucose (i.e., exceeds their transport maximum for glucose). Above a plasma glucose concentration of about 250 mg/dl, little of the extra glucose is reabsorbed by the tubules; instead, the excess glucose remains in the tubules, acts as an osmotic diuretic, and causes rapid loss of fluid into the urine. Therefore, one of the hallmarks of uncontrolled diabetes mellitus is polyuria (frequent urination), which is balanced by a high level of fluid intake (polydipsia) due to dehydration, increased extracellular fluid osmolarity, and subsequent activation of the thirst mechanism.

“LOOP” DIURETICS DECREASE ACTIVE SODIUM-CHLORIDE-POTASSIUM REABSORPTION IN THE THICK ASCENDING LOOP OF HENLE

Furosemide, ethacrynic acid, and bumetanide are powerful diuretics that decrease active reabsorption in the thick ascending limb of the loop of Henle by blocking the 1sodium, 2chloride, 1potassium cotransporter located in the luminal membrane of the epithelial cells. These “loop” diuretics are among the most powerful of the clinically used diuretics.

By blocking sodiumchloridepotassium cotransport in the luminal membrane of the loop of Henle, the loop diuretics increase urine output of sodium, chloride, potassium, and other electrolytes, as well as water, for two reasons: (1) they greatly increase the quantities of solutes delivered to the distal parts of the nephrons, and these solutes act as osmotic agents to prevent water reabsorption as well; and (2) they disrupt the countercurrent multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid. Because of this effect, loop diuretics impair the ability of the kidneys to either concentrate or dilute the urine. Urinary dilution is impaired because the inhibition of sodium and chloride reabsorption in the loop of Henle causes more of these ions to be excreted along with increased water excretion. Urinary concentration is impaired because the renal medullary interstitial fluid concentration of these ions, and therefore renal medullary osmolarity, is reduced. Consequently, reabsorption of fluid from the collecting ducts is decreased, so the maximal concentrating ability of the kidneys is also greatly reduced. In addition, decreased renal medullary interstitial fluid osmolarity reduces absorption of water from the descending loop of Henle. Because of these multiple effects, 20 to 30 percent of the glomerular filtrate may be delivered into the urine, causing urine output, under acute conditions, to be as great as 25 times normal for at least a few minutes.

THIAZIDE DIURETICS INHIBIT SODIUM-CHLORIDE REABSORPTION IN THE EARLY DISTAL TUBULE

 The thiazide derivatives, such as chlorothiazide, act mainly on the early distal tubules to block the sodium chloride cotransporter in the luminal membrane of the tubular cells. Under favorable conditions these agents may cause a maximum of 5 to 10 percent of the glomerular filtrate to pass into the urine, which is about the same amount of sodium normally reabsorbed by the distal tubules.

CARBONIC ANHYDRASE INHIBITORS BLOCK SODIUM BICARBONATE REABSORPTION IN THE PROXIMAL TUBULES

Acetazolamide inhibits the enzyme carbonic anhydrase, which is critical for the reabsorption of bicarbonate (HCO3 −) in the proximal tubule. Carbonic anhydrase is abundant in the proximal tubule, the primary site of action of carbonic anhydrase inhibitors. Some carbonic anhydrase is also present in other tubular cells, such as in the intercalated cells of the collecting tubule.

Because hydrogen ion (H+) secretion and HCO3 − reabsorption in the proximal tubules are coupled to sodium reabsorption through the sodiumhydrogen ion counter transport mechanism in the luminal membrane, decreasing HCO3 − reabsorption also reduces sodium reabsorption. The blockage of sodium and HCO3 − reabsorption from the tubular fluid causes these ions to remain in the tubules and act as an osmotic diuretic. Predictably, a disadvantage of the carbonic anhydrase inhibitors is that they cause some degree of acidosis because of the excessive loss of HCO3 − in the urine.

MINERALOCORTICOID RECEPTOR ANTAGONISTS DECREASE SODIUM REABSORPTION FROM AND POTASSIUM SECRETION INTO THE COLLECTING TUBULES

 Spironolactone and eplerenone are mineralocorticoid receptor antagonists that compete with aldosterone for receptor binding sites in the collecting tubule epithelial cells and, therefore, can decrease the reabsorption of sodium and secretion of potassium in this tubular segment. As a consequence, sodium remains in the tubules and acts as an osmotic diuretic, causing increased excretion of water, as well as sodium. Because these drugs also block the effect of aldosterone to promote potassium secretion in the tubules, they decrease the excretion of potassium. Mineralocorticoid receptor antagonists also cause movement of potassium from the cells to the extra cellular fluid. In some instances, this movement causes extracellular fluid potassium concentration to increase excessively. For this reason, spironolactone and other mineralocorticoid receptor antagonists are referred to as potassium-sparing diuretics. Many of the other diuretics cause loss of potassium in the urine, in contrast to the mineralocorticoid receptor antagonists, which “spare” the loss of potassium.

SODIUM CHANNEL BLOCKERS DECREASE SODIUM REABSORPTION IN THE COLLECTING TUBULES

Amiloride and triamterene also inhibit sodium reabsorption and potassium secretion in the collecting tubules, similar to the effects of spironolactone. However, at the cellular level, these drugs act directly to block the entry of sodium into the sodium channels of the luminal mem brane of the collecting tubule epithelial cells. Because of this decreased sodium entry into the epithelial cells, there is also decreased sodium transport across the cells’ basolateral membranes and, therefore, decreased activity of the sodiumpotassium–adenosine triphosphatase pump.

This decreased activity reduces the transport of potassium into the cells and ultimately decreases the secretion of potassium into the tubular fluid. For this reason, the sodium channel blockers are also potassiumsparing diuretics and decrease the urinary excretion rate of potassium.

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مواضيع ذات صلة

kidney Diseases

Conditions That Cause Large Increases in Extracellular Fluid Volume but with Normal Blood Volume

Conditions That Cause Large Increases in Blood Volume and Extracellular Fluid Volume

Integrated Responses to Changes in Sodium Intake

Role of Atrial Natriuretic Peptide in Controlling Renal Excretion

Role of Aldosterone in Controlling Renal Excretion

Role of Ang II in Controlling Renal Excretion

Sympathetic Nervous System Control of Renal Excretion: Arterial Baroreceptor and Low-Pressure Stretch Receptor Reflexes

Importance of Pressure Natriuresis and Pressure Diuresis in Maintaining Body Sodium and Fluid Balance

Integration of Renal Mechanisms for Control of Extracellular Fluid

Osmoreceptor-ADH Feedback System

Urine Specific Gravity