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Chapter: Modern Pharmacology with Clinical Applications: Diuretic Drugs

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Body Water and Electrolyte Metabolism

Body Water and Electrolyte Metabolism
Body fluids are partitioned between the intracellular fluids (ICF), which constitute two-thirds of total body water, and extracellular fluids (ECF), which constitute one-third of total body water.

BODY WATER AND ELECTROLYTE METABOLISM

Body fluids are partitioned between the intracellular fluids (ICF), which constitute two-thirds of total body water, and extracellular fluids (ECF), which constitute one-third of total body water. The ECF consists of plasma and interstitial fluid plus lymph. The ionic com-position differs substantially between ECF and ICF (Table 21.1). Sodium is the primary cation in ECF, whereas potassium is the principal intracellular cation.


 

The concentrations and distribution of electrolytes are not fixed, because cell membranes are permeant to ions and to water. Movement of ions and water in and out of cells is determined by the balance of thermody-namic forces, which are normally close to equilibrium. Selective changes of ion concentrations cause move-ment of water in or out of cells to compensate for these alterations. The kidneys are a major site where changes in salt or water are sensed. The loss of fluids due to ill-ness or disease may alter intracellular and extracellular electrolyte concentrations, with attendant changes in fluid movement in or out of cells. Changes of extracel-lular or intracellular ion concentrations, particularly for potassium, sodium, and calcium, can have profound ef-fects on neuronal excitability and contractility of the heart and other muscles.

Glomerular Filtration

Urine formation begins with the ultrafiltration of blood at the glomerulus. None of the available diuretics exerts its effects by altering the rate of glomerular filtration. Some agents, discussed later, reduce the glomerular fil-tration rate (GFR). However, this generally is an unde-sired or adverse reaction. Furthermore, at reduced GFRs, the delivery of sodium to the loop of Henle and the distal convoluted tubule, where the most efficacious classes of diuretics act, may be sufficiently compromised to reduce the action of the drugs. 

Understanding the process of filtration is important to understanding the pharmacokinetics of diuretic action because most of these agents exert their inhibitory effect by blocking the entry of sodium from the urine into the cell. Therefore, these diuretics have to be present at sufficient concen-trations within the tubular fluid to exert their inhibitory action on sodium transport. Most diuretics are variably bound to albumin and therefore are only partially fil-tered. They gain access to the tubular fluid by secretion into the proximal tubule (discussed later). In conditions of hemorrhage or liver disease resulting in hypoalbu-minemia, the concentration of albumin is reduced and the fraction of bound diuretic is altered. Although this may suggest that more of the diuretic is unbound (or free) and filtered at the glomerulus, this does not occur. The decrease in Starling forces, which govern the rate of fluid filtration across the glomerular and other capillar-ies, now results in greater entry of fluid into the intersti-tial space.

Most estimates of diuretic binding to albumin as-sume that the protein itself is not altered as part of the disease process. In renal failure, however, the number of binding sites on the protein may change, which in turn affects the pharmacokinetics and dynamics of the re-sponse to an administered diuretic. Another setting as-sociated with diminished effective diuretic concentra-tions occurs in nephrotic syndrome. In this disease, protein escaping from the glomerulus into the tubules binds the diuretic within the lumen. The bound drug is unavailable to exert its inhibitory effect on sodium transport.

Tubular Reabsorption and Secretion

Two additional processes that participate in urine for-mation are reabsorption and secretion. Reabsorption defines movement of solute or water from the tubule lu-men to the blood, whereas secretion denotes transport from the blood to the tubule lumen. For many solutes, such as organic acids, transport proceeds in both direc-tions. Net transport is determined by the dominant flux. As described later, the tubular secretion of some di-uretics is critical for their action. The nephron sites where ions and organic solutes are transported are spa-tially separated. Figure 21.1 illustrates the various nephron segments, the primary sites of solute transport, and the magnitude of sodium reabsorption. In some in-stances, as with sodium, several transport mechanisms mediate its reabsorption. Importantly, each mechanism is spatially separated within different nephron seg-ments. This is important in understanding diuretic ac-tion, which is specific to particular sodium transport mechanisms. Furthermore, some common side effects caused by diuretics, such as potassium wasting, develop as a direct consequence of the mechanism and the par-ticular location of diuretic action at sites upstream from the distal nephron. The emphasis of the following sec-tions is on the tubular transport properties that affect or are influenced by diuretics.


Proximal Tubule

The majority (two-thirds) of filtered NA+ is reabsorbed by proximal tubules. A number of transport mecha-nisms, including NA+ –H+ exchange, NA+ –phosphate co-transport, NA+ –glucose, NA+ –lactate, and NA+ –amino acid cotransport, participate in NA+ reabsorption. NA+ –H+ exchange is the primary mechanism of NA+ transport in the proximal tubules (Fig. 21.2). NA+ and HCO3- enter the proximal tubule after being filtered at the glomerulus. NA+ diffusion from the lumen into the cell is coupled to the extrusion of a hydrogen ion into the lumen. In the lumen, the H+ combines with HCO3- to form carbonic acid (H2CO3), which in the presence of the zinc metalloenzyme carbonic anhydrase is rapidly converted to H2O and CO2. The CO2 generated in this reaction readily diffuses into proximal tubule cells, and the process reverses. That is, the CO2 that was generated combines with intracellular water and in the presence of cytoplasmic carbonic anhydrase forms carbonic acid. The carbonic acid in turn is dehydrated to HCO3- and H+ . The HCO3- is transported across the basolateral membranes into the blood, while the H+ becomes avail-able for another cycle of NA+ –H+ exchange. The net re-sult of this process is the reabsorption of NA+ and HCO3- . Carbonic anhydrase plays a pivotal role both in the cytoplasm and in the lumen in mediating NA+ –H+ ex-change and thus in some 40% of total proximal NA+ and H2O absorption. If this enzyme is inhibited, NA+ ab-sorption is slowed because of the accumulation of H2CO3 in the lumen and the lack of H+ within the cell that can be exchanged for NA+ . Similarly, HCO3- reab-sorption is reduced with a concomitant increase of HCO3- excretion.


Several additional noteworthy features of proximal NA+ transport are relevant to diuretic action. First, since several transport proteins mediate proximal NA+ reab-sorption, no single diuretic would be expected to inhibit all these processes. Consequently, inhibition of any one mechanism leaves the others unaffected and able to continue to absorb the remaining NA+ . 

Second, NA+ that escapes proximal tubular transport is delivered to more distal nephron segments, where compensatory reab-sorption reduces the impact of diminished upstream NA+ recovery. Hence, although most NA+ is reabsorbed by proximal tubules, diuretics inhibiting its transport in this nephron segment have only a modest effect in reduc-ing overall NA+ reabsorption.

Most of the K+ that is filtered at the glomerulus is re-absorbed by proximal tubules. K+ appearing in the voided urine was secreted by distal and terminal nephron segments (discussed later).

Another significant feature of the proximal tubule is that it is the site of organic acid transport. This is im-portant in understanding both the pharmacokinetics of many of the diuretics, most of which are weak organic acids, and also certain of the side effects induced by these drugs. For instance, uric acid, which is the end product of purine metabolism in humans, is both reab-sorbed and secreted by the organic acid transport path-way .

An important functional characteristic of the proxi-mal tubule is that fluid reabsorption is isosmotic; that is, proximal reabsorbed tubular fluid has the same osmotic concentration as plasma. Solute and water are trans-ported in the same proportions as in the plasma because of the high water permeability of the proximal tubule. Thus, the total solute concentration of the fluid in the proximal convoluted tubule does not change as the fluid moves toward the descending loop of Henle. The corol-lary of this high water permeability is that unabsorbable or poorly permeable solutes in the luminal fluid retard fluid absorption by proximal tubules. This is an impor-tant consideration for understanding the actions of os-motic diuretics.

Loop of Henle

Descending Thin Limb

The descending thin limb of Henle’s loop begins at the end of the proximal straight tubule and continues past the hairpin bend in Henle’s loop to the start of the thick ascending limb. Descending thin limbs are virtually de-void of NA+ –K+ –ATPase and therefore do not participate in active sodium reabsorption. Moreover, the descending thin limb is highly impermeable to sodium and urea. Although the descending thin limb is not a site of diuretic action per se, its permeability contributes importantly to the action of osmotic agents because of its high water permeability. The presence of unabsorbable solute in the lumen retards water absorption and thereby contributes to the osmotic diuresis. Furthermore, drugs and other compounds in the tubular fluid are concentrated as a re-sult of the removal of water as the descending thin limb of long-looped nephrons passes through the hypertonic renal medulla. The elevation of drug concentrations for agents working at downstream segments may aid in rais-ing the drug concentrations to the levels necessary for di-uretic action. These elevated concentrations would not be achieved in the systemic circulation. The selective in-crease in the concentration of these drugs within the tu-bular fluid may account for the relatively selective action of these compounds on the kidney, even though the same sodium transport proteins are present in other tissues.

Thick Ascending Limb

The thick ascending limb is a major site of salt absorp-tion and a principal locus of action of an important group of diuretics. Approximately 25% of the filtered sodium is reabsorbed by the thick ascending limb of Henle’s loop. Sodium transport in this nephron segment is mediated by NA+ –K+ –2Cl- cotransport (Fig. 21.3). This transporter is present only on the apical, or urine, side of the tubule cells. Although K+ is taken up by the transporter, little net K+ reabsorption occurs in the thick ascending limb because much of the absorbed K is recycled across the apical cell membrane back into the urine. 


The recirculation of K+ is important to the generation of the electropositive voltage within the lu-men, which serves as a driving force for passive trans-port of NA+ , Ca++ , and Mg through the tight junctions joining adjacent cells. Hence, although K+ is transported by the NA+ –K+ –2Cl- cotransporter, the primary solute ab-sorbed into the blood is NaCl.

Sodium reabsorption in thick ascending limbs de-pends on the amount, or load, of salt delivered from up-stream segments. The amount of sodium reabsorbed by the thick ascending limb increases as more is delivered. In situations such as severe volume contraction, when abnormally large amounts of sodium are reabsorbed by proximal tubules, little sodium reaches the thick as-cending limb. In this setting the diuretic action of agents that block NA+ –K+ –2Cl- cotransport is impaired. This is attributable to the reduction of sodium in the tubular fluid of the thick ascending limb.

The reabsorption of NaCl by the thick ascending limb is not accompanied by water because of the low hydraulic permeability of this nephron segment. Consequently, the tubular fluid becomes dilute as it passes through the thick ascending limbs. This process contributes to normal urinary dilution. Moreover, when NA+ transport in thick ascending limbs is inhibited, uri-nary dilution will diminish.

The thick ascending limb is also an important site for the reabsorption of Ca++ and Mg . These cations are mostly passively reabsorbed through the paracellu-lar pathway between adjacent cells. The driving force for their transport is the transepithelial voltage, which is established by the rate of NA+ reabsorption. Thus, changes in voltage cause proportionate changes in the rate and magnitude of Ca++ and Mg reabsorption.

Distal Convoluted Tubule

Sodium reabsorption continues in the distal convoluted tubule, which accounts for some 6 to 8% of the trans-port of sodium. The entry of NA+ across the apical cell membrane is mediated by NA+ –Cl- cotransport (Fig. 21.4). This protein is a distinct gene product that differs from the NA+ –K+ –2C1 cotransporter in thick ascend-ing limbs.


The permeability properties of the distal convoluted tubule are regulated by antidiuretic hormone (ADH, or vasopressin). In hypotonic conditions, ADH secretion by the posterior pituitary is suppressed and the distal convoluted tubule is impermeant to water. Conversely, in hypertonic or volume-contracted states, ADH is re-leased by the posterior pituitary and increases the per-meability and water reabsorption by the distal convo-luted tubule.


The distal convoluted tubule, along with the collect-ing duct, is an important site of Ktransport. The direction (reabsorptive or secretory) and magnitude of K+ transport is governed by the metabolic state of the indi-vidual, the amount and rate of NA+ and fluid flow through the distal convoluted tubule, and the action of aldosterone. As noted earlier, the main source of uri-nary K+ is tubular secretion by distal convoluted tubules and collecting ducts. K+ secretion also increases during alkalosis and with elevated dietary K+ intake. Increases in the rate or amount of NA+ absorption or of the rate of fluid flow through the distal convoluted tubule stimulate K+ secretion into the tubular fluid. These ob-servations are especially important because they ac-count for the elevated K+ losses that attend the use of diuretics acting in more proximate segments, such as thick ascending limbs and distal convoluted tubules.

In distal convoluted tubules, calcium is transported by an active transport mechanism through rather than between cells. Moreover, in distal convoluted tubules there is a reciprocal relation between the direction and magnitude of calcium on NA+ transport. As NA+ ab-sorption increases, calcium decreases, and conversely, reductions of NA+ absorption are accompanied by ele-vated calcium reabsorption. This interaction has impor-tant implications for diuretics acting in the distal convo-luted tubule.

Collecting Ducts

The collecting ducts, which consist of cortical and medullary segments, reabsorb the final 5 to 7% of the filtered NA+ . The epithelium forming the collecting ducts consists of two distinct cell types: principal cells and intercalated cells. The relative preponderance of the two cell types varies along the length of the collecting duct and between nephron segments. Principal cells are responsible for the reabsorption of NA+ and the secre-tion of K+ (Fig. 21.5). NA+ enters the principal cell from the tubular fluid through a unique and highly selective epithelial NA+ channel, ENaC. Intercalated cells reab-sorb HCO3- and K+ and secrete H+ . Normally, H+ is se-creted into the urine and HCO3- is reabsorbed, while little net K+ transport occurs under K+ -replete conditions.


Aldosterone stimulates the rates of NA+ reabsorp-tion and K+ secretion. This is relevant to the action of spironolactone, a diuretic that is a competitive inhibitor of aldosterone (discussed later). It is also pertinent be-cause administration of diuretics can cause secondary hyperaldosteronism, which may exaggerate the potas-sium wasting that is a consequence of the increased de-livery of NA+ and enhanced flow through distal convo-luted tubules and collecting ducts.

ADH can significantly modify the total urine volume along with its solute concentration. In the absence of ADH, the collecting ducts are essentially impermeable to water. Little fluid is reabsorbed, and the final urine is dilute with respect to plasma. In other words, the clear-ance of solute-free water (CH2O) is greater than the os-molar clearance (Cosm). ADH increases water perme-ability, allowing reabsorption of fluid from the tubules into the interstitium. The driving force for water trans-port is the osmotic gradient between the medullary in-terstitium and the tubular fluid. NaCl and urea are the two major solutes accounting for the hypertonicity. The NaCl in the interstitium results from the reabsorption of NA+ by thick ascending limbs. Thus, in the absence of ADH, NA+ reabsorption contributes to medullary inter-stitial hypertonicity, water abstraction from the collect-ing ducts, and the formation of concentrated urine. Diuretics blocking NA+ reabsorption by thick ascending limbs will therefore attenuate the formation of dilute urine (CH2O) in hypotonic states when ADH is absent or low. Conversely, in hypertonic conditions, when ADH levels are high and diuretics are blocking NA+ reabsorp-tion by the thick ascending limbs, the generation of con-centrated urine is reduced, and Cosm is greater than CH2O.

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