Physiology of Diuretic Action

Objectives

Upon completion of this chapter, the student should be able to answer the following questions:

What effects do diuretics have on Na ⁺ handling by the kidneys?
What effects do aquaretics have on water handling by the kidneys?
Why do diuretics decrease the volume of the extracellular fluid?
What mechanisms are involved in delivering diuretics to their sites of action along the nephron?
What is the primary nephron site where each class of diuretics acts, and what is the specific membrane transport protein affected?
How do nephrons alter their function in response to diuretics, and how does this affect the action of diuretics?
What are the effects of the various classes of diuretics on the renal handling of K ⁺ , Ca ⁺⁺ , bicarbonate ( ${HC O_{3}}^{-}$ ${HC O_{3}}^{-}$ ), inorganic phosphate (P _i ), and solute-free water?

Key Terms

Diuretics

Natriuresis

Aquaretics

Water diuresis

Diuretic braking phenomenon

Steady state

Osmotic diuretics

Carbonic anhydrase inhibitors

Loop diuretics

Organic anion secretory system

Thiazide diuretics

K ⁺ -sparing diuretics

Organic cation secretory system

Syndrome of inappropriate antidiuresis (SIAD)

Syndrome of inappropriate antidiuretic hormone (SIADH)

Diuretics , as the name implies, are drugs that cause an increase in urine output. It is important, however, to distinguish this diuresis from that which occurs after the ingestion of large volumes of water. In the latter case the urine is primarily made up of water, and solute excretion is not increased. In contrast, diuretics result in the enhanced excretion of both solute and water.

All diuretics (with the exception of aquaretics, which will be discussed) have as their common mode of action the primary inhibition of Na ⁺ reabsorption by the nephron. Consequently, they cause an increase in the excretion of Na ⁺ , termed natriuresis . However, the effects of diuretics are not limited to Na ⁺ handling. The renal handling of many other solutes also is influenced, usually as a consequence of alterations in Na ⁺ transport. Drugs have been developed that block the action of arginine vasopressin (AVP) on the distal tubule and collecting duct. These drugs, called aquaretics , cause a water diuresis . This chapter reviews the cellular mechanisms of action of various diuretics and the nephron sites at which these diuretics act. In addition to their effects on Na ⁺ handling by the nephron, their effects on the renal handling of other solutes (e.g., K ⁺ , Ca ⁺⁺ , inorganic phosphate [P _i ], and bicarbonate [ ${HC O_{3}}^{-}$ ${HC O_{3}}^{-}$ ]) and of water are considered. The effects of aquaretics on water excretion also are discussed.

General Principles of Diuretic Action

The primary action of diuretics is to increase the excretion of Na ⁺ . As described in Chapter 6 , alterations in Na ⁺ excretion by the kidneys result in alterations in the volume of the extracellular fluid (ECF) compartment. Consequently, diuretics decrease the volume of the ECF. Indeed, diuretics commonly are given in clinical situations when the ECF compartment is expanded, with the intent of reducing its volume. Because the ECF volume also determines blood volume and pressure, diuretics commonly are used in the therapy of hypertension.

Although generally predictable for a particular class of diuretics, the effects of diuretic administration can be quite variable. Several factors are important in determining the overall effect of a particular diuretic:

1.
The nephron segment where the diuretic acts
2.
The response of nephron segments not directly affected by the diuretic
3.
The delivery of sufficient quantities of the diuretic to its site of action
4.
The volume of the ECF

Sites of Action of Diuretics

Fig. 10.1 depicts the nephron sites at which the different classes of diuretics act. The osmotic diuretics act along the proximal tubule and portions of the thin descending limb of Henle’s loop (i.e., those portions of the nephron that have a high water permeability). The carbonic anhydrase inhibitors act primarily in the proximal tubule. The thick ascending limb of Henle’s loop is the site of action of the loop diuretics. The early portion of the distal tubule is the site of action of the thiazide diuretics, and the K ⁺ -sparing diuretics act primarily on the late portion of the distal tubule and the cortical portion of the collecting duct (i.e., the aldosterone-sensitive distal nephron [ASDN]) where they inhibit not only Na ⁺ reabsorption but also K ⁺ secretion. The K ⁺ -sparing diuretics also can inhibit Na ⁺ reabsorption in portions of the collecting duct that do not secrete K ⁺ .

The site of action of a diuretic in turn determines the magnitude of the associated natriuresis ( Table 10.1 ). For example, diuretics acting on the thick ascending limb of Henle’s loop cause a larger diuresis than diuretics acting on the early portion of the distal tubule, because a larger portion of the filtered Na ⁺ is reabsorbed by the thick ascending limb (see Chapter 4, Chapter 6 ). The effect diuretics have on the handling of solutes other than Na ⁺ also depends on the site of action. Examples illustrating this point are given in subsequent sections.

TABLE 10.1

Diuretic Effects on Renal Excretion

Diuretic	Na ⁺ Excretion ^∗	K ⁺ Excretion	${HC O_{3}}^{-}$ ${HC O_{3}}^{-}$ Excretion	Ca ⁺⁺ Excretion	Free Water Excretion	Free Water Reabsorption
Osmotic diuretic	10%	↑	↑	↑	↑	↑
CAI	5%–10%	↑	↑	↑	↑	↑
Loop diuretic	25%	↑	↓	↑	↓	↓
Thiazide diuretic	5%–10%	↑	↓	↓	↓	NC
K ⁺ -sparing diuretic	3%–5%	↓	↑	NC	NC	NC
Aquaretics	0%	NC	NC	NC	↑	↓

CAI, Carbonic anhydrase inhibitor; NC, no change.

All the effects (except

{HC O_{3}}^{-}

${HC O_{3}}^{-}$ excretion) reflect the initial effect of the diuretic. The effects of loop and thiazide diuretics on

{HC O_{3}}^{-}

${HC O_{3}}^{-}$ excretion occur with prolonged use of these drugs and are secondary to the diuretic-induced decrease in extracellular fluid volume.

∗ Percentage of filtered Na ⁺ excreted into the urine

Response of Other Nephron Segments

When a diuretic inhibits Na ⁺ reabsorption at one nephron site, it causes increased delivery of Na ⁺ and water to more distal segments. The function of these more distal segments and their ability or inability to handle this increased load ultimately determine the overall effect of the diuretic on urinary solute and water excretion. Examples of this phenomenon are considered in detail with discussion of each of the various diuretics. In addition, diuretic-induced changes in ECF volume (discussed later in this chapter) may modulate Na ⁺ transport in segments of the nephron not directly affected by the diuretic and thereby influence the degree of natriuresis.

Adequate Delivery of Diuretics to Their Site of Action

The effect of a diuretic on Na ⁺ excretion also depends on the delivery of adequate quantities of the drug to its site of action. With the exception of the aldosterone antagonists, which act intracellularly, diuretics act from the lumen of the nephron (carbonic anhydrase inhibitors have both luminal and intracellular sites of action). Diuretics gain access to the lumen by glomerular filtration and through secretion by the organic anion and organic cation secretory systems located in the proximal tubule (see Chapter 4 ). Because some diuretics are bound to plasma proteins (e.g., loop diuretics), their secretion by the proximal tubule is the primary mechanism for delivery of the diuretic to its site of action in the lumen of the nephron. Thus the effect of a diuretic can be blunted if, for example, it is administered with another drug that competes for the same organic anion and organic cation secretory mechanism.

Volume of the Extracellular Fluid

The effect of a diuretic also depends on the volume of the ECF. As described in Chapter 6 , when the volume of the ECF is decreased, the glomerular filtration rate (GFR) is reduced, thereby reducing the amount of filtered Na ⁺ . In addition, Na ⁺ reabsorption by the nephron is enhanced. Thus the effect of a diuretic that acts on the distal tubule would be blunted if administered in the setting of a reduced ECF volume. Under this condition, the decreased GFR (i.e., decreased filtered Na ⁺ ), together with enhanced Na ⁺ reabsorption by the proximal tubule, would result in the delivery of a smaller quantity of Na ⁺ to the distal tubule. Thus even if the diuretic completely inhibited Na ⁺ reabsorption in the distal tubule, the associated natriuresis would be less than would occur if the ECF volume were normal.

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