Principles

and Clinical Salim K. Mujais,

Uses of Diuretic

Nancy A. Nora, and Murray

NDUCTION OF diuresis as a therapeutic modality has long been a mainstay of medical practice. It was advocated by physicians in the Fertile Crescent for the treatment of many renal diseases. Components capable of inducing diuresis have been identified in Sumerian, Assyrian, and Babylonian pharmacopeias.’ More recently, Al-Rhazi (850-932 AD), chief physician in Bagdad in the Abbasid period, prescribed it to prevent obstruction in cases of renal papillary necrosis,’ and Ibn-Sina (Avicenna) (980-1037 AD) incorporated diuresis as an integral part of his regimen for the dissolution of kidney st0nes.j Even Withering prescribed foxglove thinking it was a diuretic. However, modern diuretic therapy finds its origins in fortuitous observations on agents first introduced as antimicrobials. Vogl in I920 reported the diuretic effect of the organomercurial merbaphenum, then a treatment for syphilis. However, mercurials proved to be highly toxic and inconvenient. The need for a safer orally effective diuretic was satisfied with a second astute observation from the field of antimicrobials. Benzothiadiazine diuretics were discovered after the observation of diuresis during antimicrobial therapy with sulphonamides. In 1957, Novello and Sprague synthesized chlorothiazide and ushered the era of widespread use of diuretics into the practice of medicine.

I

GENERAL Renal

PRINCIPLES

Physiological

OF DIURETIC

THERAPY

Principles

Two basic principles of renal tubular physiology are relevant to a discussion of diuretic therapy: segmental organization of the nephron and axial integration of transport along the nephron. These principles allow a proper understanding of the mechanism of action of diuretics and present a framework for discussing the limitations of some diuretics and the proper use of combined diuretic therapy. SegmentalOrganization

Sodium transport has varying rates and is linked to different secondary transport processes in the different nephron segments. Although a detailed examination is beyond the Progress

m Cardiovascular

Diseases,

Vol XXXV,

No 3 (November/December),

Therapy

L. Levin

scope of this review, characteristics of segmental transport relevant to diuretic therapy will be addressed briefly. Transport of sodium in the proximal convoluted tubule can be divided into two phases: entry into the cell via the luminal membrane and exit via the basolateral membrane. The latter process is affected primarily by the sodium pump, Na-K-ATPase (adenosine triphosphatase).4 At the luminal side, sodium is involved in a series of “pas de deux” with many solutes (Fig 1). The transport of glucose, phosphate, sulfate, carboxylic acid, and amino acids is intimately linked to luminal sodium entry.“,” Hence, interference with sodium transport in this nephron segment would be expected not only to increase distal delivery of sodium, but also to interfere with the transport of some of the solutes linked to sodium transport. In addition to these co-transport mechanisms, sodium also enters the proximal tubular cell in a 1:1 exchange for hydrogen ion by a carrier termed the Na+-H+ antiporter.’ The proximal convoluted tubule is also involved in the secretion of organic acids and bases. Many diuretics gain access to the lumen of the tubule by competing for the same transport mechanisms as organic acids.x Thus, access of diuretics to their site of action can be modified by factors that either block or saturate these mechanisms. The basic mechanisms of sodium transport are similar in the medullary and cortical thick ascending limbs of Henle’s loop despite morphologic and permeability differences. Thick ascending limbs reabsorb NaCl at a rapid rate. The mechanism can again be best understood by separating this reabsorptive process into luminal plasma membrane entry and basolateral exit phases. At the latter membrane, the mechanism of Na exit is again mediated by Na-K-ATPase as

From Medical Lakeside Address

the Depurtment School. and Medical reprint

Center, requests

of Medicine, the

Department Chicago, to Salim

North western Unicrrsi~ of C’eteraru Affairs. IL. K. Mujais.

MD,

Section

Nephrology. C7A Lakeside Medicul Center. 3.3.3 E Huron Chicago. IL 60611. Copyright R 1992 by W. B. Saunder.r Cornprr~~~ 0033.0620!9213503-000~$5.00!(~

1992:

pp 221-245

oJ St.

221

MUJAIS,

222

w

Na

Amino acids Na

K

--b

Na

Glucose

Fig 1. convoluted transport

Model of the transport tubule cell showing systems.

AND

LEVIN

Cl- but of the passively absorbed cations (calcium and magnesium) as well.” Sodium reabsorption along these segments has another role: it dilutes the tubular fluid by the removal of solute while water remains within the lumen because of low water permeability. The ascending limb also provides the driving force for the generation of the osmotic gradient that is maintained by the countercurrent mechanism and thus is responsible for the ability to concentrate the urine.“,‘” Thus, interference with sodium transport in the thick limbs can alter water handling by the kidneys. Sodium reabsorption in the distal convoluted tubule is mineralocorticoid independent and results in a lumen negative potential difference.r5.1h Active Ca reabsorption occurs in this segment and is modulated by parathyroid hormone (PTH). By inhibiting Na reabsorption in the distal convoluted tubule (DCT), thiazides lower cellular Na concentration and inhibit the lumen negative potential. This enhances sodium entry into the cell by Na/Ca exchange across the basolateral membrane, favoring basolateral calcium exit. The resultant decrease in cell calcium favors luminal Ca entry. The net effect is enhanced Ca reabsorption by the DCT. which forms the basis for the use of thiazides in the treatment of nephrolithiasis.” The collecting tubules are of a different embryologic origin from more proximal segments and contain a combination of different cell types mixed and interspersed. Transport in

:): K

Na

NORA,

pathways dependence

in the proximal on Na of many

in other nephron segments. Enzyme activity in thick ascending limbs is one of the highest per unit length along the nephron.4.’ At the luminal side, Na entry is effected by means of a transporter that couples the entry of one sodium ion and one potassium ion to two chloride ions (Fig 2).l” This transporter is driven by the concentration gradient for sodium created by the active transport of sodium at the basolateral membrane by Na-K-ATPase. The transported chloride exits from the cell via basolateral pathways. Potassium reenters the lumen via conductive pathways along the luminal membrane. The recycling of potassium (positive charge) back to the lumen and the basolateral negative chloride current, create a positive voltage inside the lumen.rl This positive transepithelial voltage along with high permeability for cations through tight junctions and lateral intercellular spaces drive passive transport of Ca, Mg, and ammonia. The large reabsorptive fluxes for Ca and Mg in this region of the nephron account for a major part of their total renal tubular reabsorption. Therefore, inhibition of sodium transport by diuretics acting at this site would be expected to alter the reabsorption of these cations. Indeed, loop diuretics like furosemide compete with chloride for the lumen transporter and thereby inhibit sodium transport resulting in increased urinary excretion, not only of Na+ and

K

K Na 2c1

Ca m Fig 2. Model of the transport ing loop of Henle.

pathways

in the thick

ascend-

DIURETIC

THERAPY

223

the cortical segment of the collecting tubule is driven primarily by basolateral Na-K-ATPase (Fig 3). Sodium entry occurs through conductive channels at the luminal membrane.r8 The reabsorption of sodium generates a lumen negative voltage that enhances potassium exit via K-conductive pathways in the luminal membrane and hydrogen ion secretion via a protontranslocating ATPase located at the luminal membrane.‘” Potassium and hydrogen ion secretion in this segment can be enhanced by increased sodium delivery and inhibited by blockade of sodium transport. Diuretics acting proximal to the cortical collecting tubule will increase sodium delivery to this segment, and thus enhance potassium and hydrogen ion secretion and lead to hypokalemia and metabolic alkalosis. Diuretics such as amiloride that block luminal sodium channels will decrease potassium and hydrogen ion secretions. The outer medullary collecting duct has no appreciable sodium transport, and thus its transport func-

Na Y

I -H+ >

Fig 3. ing tubule

Model cell.

of the transport

H2O

pathways

in a cortical

collect-

tion is mostly related to hydrogen ion secretion and water transport and is not directly affected by diuretics. lx The papillary collecting ducts reabsorb sodium chloride, a process that is probably inhibited by atria1 natriuretic factors~““21

Axial Integration The capacity for sodium transport varies along the nephron with segments capable of high transport rates being followed by segments with lower transport capacity. The high transport rates of the early segments allows them to react rapidly to changes in the filtered load of sodium and lead to effective stabilization of sodium delivery to the last nephron segments where the final concentration of urine sodium is determined. This stabilization of distal delivery of sodium is required to allow more efficient transport by segments with both low transport capacity and less tubule mass, the latter a result of the confluence of several nephrons into the collecting tubules. Stabilization of distal delivery also sets ideal conditions for hormonal modulation of transport in the final nephron segments. This continuity and interdependence of nephron segments is also exemplified by the observation that transport in many segments is altered by the composition and rate of tubular fluid delivery from more proximal segments. Hence, alteration in sodium transport in proximal segments alters distal transport and may be offset by those alterations. This would explain the relative ineffectiveness of diuretics that act in the proximal tubule because this segment is followed by the thick ascending limb of Henle’s loop, a segment with high reabsorptive capacity that can vary its transport with delivered load. Interruption of distal compensation for proximal events is the basis of combined diuretic therapy (see section on Principles of Diuretic Therapy). Another example of alteration in distal function secondary to proximal events is the kaliuresis associated with diuretic therapy. Increased sodium delivery to the cortical collecting tubule consequent to a proximal diuretic effect enhances potassium secretion and leads to negative potassium balance.

224

Hormonal

MUJAIS,

Influence

Three hormones are of relevance to the renal actions of diuretics: aldosterone, angiotensin, and vasopressin. Aldosterone. Binding sites for aldosterone have been identified in the cortical and medullary collecting tubules, and the direct effects of the hormone are generally restricted to these segments.” At the level of the cortical collecting tubule, aldosterone has three major effects: (1) it enhances sodium permeability of the luminal membrane by increasing the synthesis of permease proteins that act as sodium conductive pathways, (2) chronic administration leads to stimulation of basolateral Na-K-ATPase,‘“-“I and (3) in analogues of the collecting duct, the hormone increases the production of ATP.” All of these effects appear to be geared to optimize sodium transport in this segment. However, it should be noted that although these three effects are interrelated, they can occur independently. The increase in luminal sodium conductive pathways is an early effect of aldosterone and can occur before any changes in the other effects are apparent. The stimulation of Na-KATPase is a time-requiring effectZx that is not prevented by chronic blockade of luminal sodium entry by amiloride or by cellular ATP depletion.Z4 The net physiological effect of aldosterone at this segment is to enhance sodium reabsorption. This leads to an increase in the lumen-negative potential difference that potentiates the secretion of potassium and hydrogen ions. At the level of the medullary collecting tubule, aldosterone leads to an enhancement of acidification that is sodium independent and may be facilitated chronically by stimulation of proton-ATPase.iq Chronic diuretic therapy (except with aldosterone antagonists) is associated with secondary hyperaldosteronism, the degree of which may be modified by the underlying disease, administration of other drugs (prostaglandin inhibitors, converting enzyme inhibitors), and dietary sodium intake. The increase in aldosterone level is secondary to the diureticinduced increase in renin levels. This secondary hyperaldosteronism plays a major role in magnifying diuretic side effects (hypokalemia, alkalosis) and in blunting diuretic response. Angiotensin. Receptors for angiotensin II have been identified in the renal vasculature, in

NORA,

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glomeruli, in discrete nephron segments, and in interstitial medullary cells? Direct effects of the hormone have been documented at all of these sites. Angiotensin I1 receptors in the renal vasculature mediate the effects of the hormone on renal hemodynamics. The hormone leads to an increase in renal vascular resistance and a decrease in renal blood flow. Because of the peculiar greater sensitivity of the efferent arteriole as compared with the afferent arteriole to the vasoconstrictor effect of the hormone, angiotensin II maintains filtration pressure and attenuates the decrease in GFR elicited by decreased renal blood flow. Angiotensin II affects the glomerulus directly by inducing the contraction of mesangial cells and thereby decreasing the filtering surface of the glomerular capillary bed. The tubular effects of angiotensin II have long been a subject of controversy. However, recent studies have documented specific angiotensin 11 receptors in distinct segments of the nephron.“” The net effect of angiotensin II in physiological concentrations is to increase salt and water reabsorption directly in the proximal convoluted tubu1e.j’ The extrarenal effects of angiotensin II are also of importance because the hormone is the most important regulator of aldosterone secretion from the adrenal gland, and its level modulates the influence of other aldosterone secretagogues. The increase in angiotensin II levels that occurs with diuretic therapy can thus influence renal function in a multifactorial fashion in sum geared towards conservation of salt and water and protection of the volume of the extracellular space. This increase in angiotensin II will modify the therapeutic response to diuretics in many clinical conditions. In hypertensive patients, the secondary hyperreninemia and increased angiotensin II levels will blunt the antihypertensive effect of the diuretics. In congestive heart failure, the increased circulating levels of angiotensin II will lead to peripheral vasoconstriction and increased afterload. They also enhance proximal reabsorption as described above. The high levels of angiotensin II will stimulate aldosterone production, and the mineralocorticoid effect of the hormone wiil diminish the natriuresis of diuretic agents by increasing sodium transport in the collecting tubule.3L Vasopressin. The importance of considering

DIURETIC

225

THERAPY

vasopressin in a review of diuretic therapy is highlighted by the fact that the respective effects of vasopressin and diuretics are intimately related. The ability to concentrate the urine in response to vasopressin is dependent on active sodium transport in the thick ascending limb that energizes the creation of medullary hypertonicity. Therefore, the optimal response to the vasopressin-induced increase in water permeability in the collecting duct can be blunted by loop diuretics that impair the ability to create medullary hypertonicity. Furthermore, vasopressin levels are increased in many of the conditions in which diuretics are used, and diuretics may influence the release of the hypophyseal hormone. Finally, diuretics are often used in conditions of either vasopressin excess, renal unresponsiveness to vasopressin, or vasopressin deficiency. The influence of diuretics on vasopressin levels is multifactorial. Hypovolemia, if significant, can lead to increased release of vasopressin from the hypophysis by activation of receptors in the central circulation. The relationship between the hypovolemic stimulus and hormone release is exponential. Little vasopressin is released with decreases in blood volume of less than 8%. Beyond a 10% decrease in blood volume, the levels of vasopressin increase sharply and progressively. Therefore, mild hypovolemia with usual diuretic therapy is not expected to alter vasopressin levels significantly. Diuretics may affect vasopressin levels indirectly by increasing the levels of circulating angiotensin II, a known stimulant of vasopressin release, but the levels of angiotensin II required to enhance vasopressin release are high and may not be readily achieved with usual diuretic therapy. Finally, the changes in plasma osmolality that may occur with diuretic therapy, notably hyponatremia, may alter the release of the hypophyseal hormone. Principles

of Diuretic

Therapy

Sites and Mechanisms of Action The sites of action of diuretics are determined by their mechanisms of inhibition of transport and the location of the specific transport system along the nephron (Table 1). Hence, the site of action of carbonic anhydrase inhibitors is dependent on the distribution of the

Table

1. Mechanism

and

Target

Nephron

Target System

Diuretic

Site

of Diuretics

Target Segment

Acetazolamide

Carbonic

anhy-

Proximal

Loop

drase Na-K-2CI

co-trans-

Thick ascending limb

diuretics

Thiazides azide-like Amiloride

and thi-

port Na-Cl co-transport

and tri-

Na channels

Cortical

collecting

Aldosterone

tubule Cortical tubule

collecting

amterene Spironolactone

tubule

ceptor

re-

Distal convoluted tubule

enzyme along the nephron and the role played by the enzyme in sodium transport. Similarly, the site of action of diuretics that inhibit the Na-K-2Cl transporter is the segment where this transporter is localized, namely the luminal membrane of the thick ascending limb of Henle’s loop. The sites of action of diuretics also determine the degree of natriuresis and compensatory responses. Thiazides, for example, act at a segment where only 8% of the filtered load of sodium is reabsorbed. The resultant diuresis is decidedly modest. Loop diuretics (furosemide, ethacrynic acid, piretanide, and bumetanide) inhibit NaCl transport in the thick ascending limb of Henle’s loop by binding specifically and reversibly to the chloride-binding site of the luminal transporter responsible for the coupled entry of Na-KC1.33-3f’ Furosemide, piretanide. and bumetanide also inhibit sodium transport in the proximal convoluted tubule (PCT) by a mechanism independent of the inhibition of carbonic anhydrase and may affect chloride permeability at sites distal to the thick ascending limb.35-3x The primary site of action of thiazides is in the distal convotuted tubuIe where they inhibit NaCl cotransport. Ii-. I6 Thiazides may also have an effect on NaCl reabsorption in the late proximal tubule. This proximal effect of thiazides is not appreciated in the usual clinical setting because any decrease in Na reabsorption in the proximal tubule would be negated by the reabsorptive capacity of the thick ascending limb of the loop of Henle. Amiloride and triamterene block Na channels in the cortical collecting tubule.3q-4’ The resulting decrease in Na reabsorption reduces the transepithelial electrical potential, the factor that normally favors potassium secretion.

226

This is the basis for the hyperkalemic effect of these drugs. In the cortical collecting tubule, the secretion of protons by H+-ATPase located in the luminal membrane is also voltage facilitated and reduction in the luminal negativity will decrease proton secretion in this segment. In fact, administration of amiloride leads to an increase in urine pH, but the effect has no clinical significance because the acid-base balance is not significantly affected. The sodium channel blocked by amiloride also facilitates the entry of lithium into the cell from the lumen. This forms the basis for the recent suggestion that Na-channel blockers may be useful in the treatment of lithium-induced nephrogenic diabetes insipidus (DI) probably by reducing the accumulation of lithium in the cortical collecting tubule (discussed later).“’ Access to Site of Action With the exception of carbonic anhydrase inhibitors and aldosterone antagonists, the major diuretics act from the tubular lumen directly to inhibit transport mechanisms in the luminal membrane.“” Depending on the degree of protein binding, some diuretics will reach the lumen by glomerular filtration. Because only the unbound fraction is freely filtrable, only a small percentage of highly protein-bound diuretics will reach the tubular lumen through filtration. More important, by virtue of their chemical nature, many diuretics will be secreted into the lumen by either the organic acid or organic base transport system of the proximal tubule.43.44 This mode of entry to the lumen is also affected by protein binding to a certain degree. There is an inverse interplay between the effect of protein binding and the affinity of the tubular transporter for the diuretic.45,4h The affinity of the transporter for thiazides is very high and the excretion of the diuretic cannot be increased by a change in protein binding. In contrast to glomerular filtration, renal tubular secretion is a saturable process. Consequently, tubular secretion of a diuretic can be reduced by competitive inhibition from endogenous (as in renal failure) or exogenous (other drugs) organic acids.47 Factors Modifjling Diuresis Several factors can modify the therapeutic response expected from the administration of a

MUJAIS,

NORA,

AND

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particular diuretic. First, inhibition of solute transport in one portion of the nephron can be nullified by compensatory changes in transport by other nephron segments. Second, delivery of an inadequate quantity of the drug to its site of action can modify the expected effect of a diuretic (as discussed previously). Third, attainment of an appreciable diuretic response requires adequate delivery of solute and fluid to the tubule. If renal perfusion or glomerular filtration is compromised, the degree of diuresis will be markedly blunted. Renal Compensatory Responses to Diuretics Drug-induced diuresis is inherently selflimited. Intrarenal adjustments to the reduction in extracellular fluid volume occur to prevent the development of severe depletion. Solute and water reabsorption increase in segments of the nephron not altered pharmacologically by the drug. This enhancement in reabsorption can occur in unaltered segments either proximal or distal to the site of action of the drug. In the case of proximally acting diuretics, the increase in salt delivery is met very proficiently by the ascending limb of Henle as to obliterate the diuretic response almost completely. A notable conserving mechanism that is operable with many diuretics is the secondary hyperaldosteronism that increases sodium reabsorption in the collecting tubule. The intra- and extra-renal adjustments to diuretics slow down the urinary excretion of salt and water.4x This phenomenon has been labeled the “braking phenomenon” by Grantham and Chonko and may be the converse of the “escape phenomenon” observed with mineralocorticoid excess.4y,5(1 This is a conceptually and practically very appealing concept that describes the occurrence of a new steady state at a new level of total body sodium. It is the mirror image of the “escape phenomenon” and like it expresses a point of salt balance. The mechanism for “braking” varies with different diuretics depending on their site of action. For proximal diuretics it is mediated by enhanced reabsorption in the loop and the distal segments. For loop diuretics, the braking is brought about by enhanced reabsorption in the proximal tubule secondary to decreased glomerular filtration rate (GFR) and renal plasma flow and by increased distal mineralocorticoid effect.‘]

DIURETIC

THERAPY

Combined Diuretic Therapy The segmental localization of the effects of diuretics endows each agent with particular properties and side effects. It may also limit the effectiveness of a diuretic in altering Na balance. It has already been noted how a proximal inhibition of sodium transport can be compensated by reabsorption downstream. However, the segmental peculiarity of diuretic effects can be used to enhance natriuresis by combining diuretics that work at different sites. A popular form of this combination therapy is that of using loop agents and thiazides or thiazide-like drugs. This combination prevents the compensatory distal increases in Na reabsorption that limit the effectiveness of loop agents.‘*-“’ The overall result can be a profound diuretic effect that is greater than that achieved with either agent alone. By enhancing diuresis, this form of therapy also increases the side effects of diuretic therapy leading to volume depletion, severe hypokalemia, and metabolic alkalosis. Careful monitoring and judicious dose adjustment are required to avoid serious complications. Combination therapy can also be used to limit the kaliuretic effects of diuretics. A major mechanism of potassium wasting with diuretic therapy is enhanced potassium secretion by the cortical collecting tubule (see following section for details). This occurs through the interplay of increased Na delivery to this segment, increased Na reabsorption, and increased circulating levels of aldosterone.‘” Addition of a sodium channel blocker to a diuretic regimen will block sodium reabsorption and therefore decrease the secretion of potassium. Similarly, addition of an aldosterone antagonist will block the effect of the hormone at this segment and reduce the kaliuresis.ssJ9 These combinations have proven to be very useful in clinical practice and are commonly available in fixed dosage forms. Resistance to Diuretics The list of clinical conditions in which resistance to diuretics has been described is similar to a list of the most common indications for the use of diuretics.h”-h” This paradox invites examination of the concept of resistance to diuretics and elucidation of the factors responsible for true resistance and those leading to pseudoresis-

227

tance. True resistance to diuretics can be defined as a state where administration of a diuretic in proper dosage and with proper attention to pharmacokinetic principles fails to elicit the expected diuretic response in a patient with a condition usually responsive to this form of therapy. Such a true resistance is fortunately rare, and the vast majority of patients with “resistance” to diuretics have a pseudoresistance. Clinically, however, uncovering the causes of pseudoresistance can be a challenging undertaking for the physician. The approach to resistance to diuretics resides in posing the question, “Is it the patient, the physician, or the kidney that is resistant to diuretic therapy?“h5 The most common patient-related resistance factors are noncompliance and excessive salt intake.4xs6hThe former is the most common form of pseudoresistance to all known drugs and therapies. The latter is of particular importance in diuretic therapy because the effectiveness of these drugs can be blunted by high salt intake and the severity of their side effects, particularly hypokalemia, is thereby increased. Physician-related resistance factors include the use of inappropriate dosage forms or simultaneous prescription drugs that blunt the diuretic effect. An example of the former is the use of hydrochlorothiazide alone in a patient with a glomerular filtration rate (GFR) below 30 mlimin. An example of the latter is simultaneous prescription of furosemide and a nonsteroidal antiinflammatory drug for an elderly patient with congestive heart failure and low back pain or requiring other drugs.‘17-h” Kidney-related resistance can be divided into two categories: impaired access of the diuretic to its site of action (pharmacokinetic resistance) and blunted organ responsiveness to the diuretic (pharmacodynamic resistance). The factors affecting access of a diuretic to its site of action have been described above. An important issue relates to the quantitative aspects of diuretic access. The degree of diuresis elicited by a diuretic agent is determined by the amount of drug reaching the site of action. Of equal importance is the time course of that delivery to the site of action. Attention to pharmacokinetic principles is clearly of great importance in dissecting the cause of diuretic resistance.h’ Disease states requiring diuretic therapy often

MUJAIS,

lead to modification of drug access to tubular sites of action and the quantitative aspects of this delivery. Diuretic resistance can be encountered in azotemia because endogenous organic acids compete with diuretics for the active secretory mechanisms in the proximal convoluted tubule, and a larger dose of diuretics are required to achieve a response.‘” In other disease states, the dose-response relationship may be altered because the disease may induce altered transport characteristics in the kidney that thwart the effect of diuretics: decreased solute delivery to site of diuretic action by reduction of GFR or enhanced reabsorption by segments proximal or distal to that site. Finally, intestinal absorption of diuretics may be impaired in severely edematous patients.h’ An attempt at defining the mechanisms of resistance to a diuretic should be undertaken before changes in therapy are made. Correcting patient noncompliance, dietary indiscretion, or dose to be administered will solve many cases of pseudoresistance. Attention to drug interference will further reduce the number of cases. When resistance is still encountered, the approach should be to determine first whether adequate amounts of the drug are reaching the target organ. This can be done empirically by attempting a gradual increase in dose until a satisfactory response is achieved, or a ceiling dose is reached.h3 However, this carries a risk of drug toxicity and should be attempted with extreme caution if one is contemplating using large doses of toxic drugs. Alternatively, one can measure drug concentrations in the urine and, if adequate amounts are reaching the site of action, one avoids toxicity by refraining from increasing the dose. If it is determined that adequate amounts of drug are available, then the next step is to determine which disease mechanism is responsible for the blunted diuresis. If hyperaldosteronism is present, then use of aldosterone antagonists or sodium channel blockers can be successful. In some cases, modifying the disease-related renal changes will improve the response to diuretics. For example, the use of dopamine will increase renal blood flow and GFR and restore some of the response to diuretics in patients with liver cirrhosis and ascites. A useful therapeutic guideline in resistance

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to diuretics is patience, “a small word but a large attitude.““5 Diuretic therapy in most cases should be performed in a deliberate manner with individualization of care. Such individualization should allow proper consideration of the condition being treated, the goal to be achieved, and the proper means to achieve it. It can never be overemphasized that “il n’y pas de maladic mais des malades.” CLINICAL

PHARMACOKINETICS

OF DIURETICS

The clinical effectiveness of a diuretic is dependent not only on its site of action but also on its rate of absorption, peak serum level, rate of excretion, serum half-life, onset of action, etc. This constellation of pharmacologic variables constitutes the pharmacokinetics of the diuretic agents. hi However, the onset of action, magnitude of response, and duration of response to these agents may be altered significantly as noted previously by intrarenal functional adjustments to volume status, circulating hormones, primary disease states, and drug interactions. These physiologic and pathophysiologic alterations affect the pharmacodynamics (ie, renal response to a dose or circulating level of drug) to a great extent and must be considered when a diuretic is administered. The usual pharmacokinetic data of the commonly used diuretics are listed in Table 2. Because of space considerations, only examples of commonly used loop agents, thiazide, thiazidelike, and potassium-sparing agents are listed in the table. As mentioned previously, many disease states and drugs alter the renal response to diuretic agents. The dose of diuretic needed to effect an appreciable diuresis is significantly altered by the presence of renal insufficiency.” Many studies have demonstrated the requirement for larger and larger doses of a diuretic as renal insufficiency progresses.7’-74 One probable reason for this is the displacement of drugs from binding sites on serum proteins by retained organic anions and competition by these anions with the diuretic for secretion into the tubular lumen.7”,73 If secretion of the drug is inhibited, the diuretic is prevented from reaching its cellular site of action, the luminal surface of the tubular epithelial cells. Thus, when the GFR is less than 10 mlimin, the half-life of furosemide

DIURETIC

THERAPY

229

Table

Diuretic

Acetazoiamide

2-4

Amiloride Bumetanide Chlorthialidone Ethacrynic

acid

Furosemide Hydrochlorothiazide lndapamide Metolazone Spironolactone Triamterene

Half-life brmall (h)

2. Pharmacokinetics

of Selected

Diuretics

Protein Binding

Interval

W)

(h)

Method

79-90

6 12-24

I D

no A

D I

no A n0.i

no A no A

5-10 5-10 12.5-100 25-200 20-320

DOW

Dose Adjustment

by Method

and GFR

GFR > 50

6

10.50

(mgidl

12* 50%X

250-750

6-9.5 1.2-1.5

O-10 96

50-80

90

6 24

90 95

6 6

I D

no A no 3

no 1 no A

6-8 14-18 12-14

20-80 76-79 95

12 24 24

D D D

no A no A

n0.I noA

10-35 1.5-2.5

98 40-70

6 12

I D

no A no h

no A 12* 50%f

2-4 .3-1.6

Abbreviations: D, dosage adjustment; I, internal *Use with extreme care and avoid if alternative

DOSlZ

Range

no A

12.5-100 2.5-5.0 2.5-20.0 25-100 50-100

adjustment; A, change. treatment is effective.

can be as long as 9 to 10 hours.” The dose required for inhibition of sodium chloride and potassium chloride entry into the cell is considerably greater than that required when renal function is normal. Additionally, the fractional excretion of sodium per nephron is quite high in chronic renal insufficiency. An even greater degree of inhibition of electrolyte reabsorption than that in normal function will be necessary to cause a significant increase in sodium excretion and urine flow. Thus, weaker diuretics, such as the thiazides, become ineffective when GFR is less than 30 mL/min. Patients with nephrotic syndrome may also show a relative refractoriness to diuretics. Although altered renal tubular function such as enhanced proximal and distal salt and water reabsorption may play an important role, the large quantities of intraluminal protein present in nephrotic urine bind significant quantities of diuretics.45 Thus, the diuretic will not be available to inhibit solute reabsorption. In addition, the hypoalbuminemia associated with nephrosis allows for less protein binding and, secondarily, less proximal tubular secretion of drug.4h.75-7XIt follows that some hypoproteinemic patients have improved response to furosemide when the drug is bound to albumin before infusion because the protein-bound drug can be secreted into the tubular lumen more readily.4h Furosemide absorption is diminished in patients with decompensated congestive heart failure.h2 Also, the dose-response curve is shifted to the right in many patients with congestive failure. This abnormality is not always corrected

when the heart failure becomes compensated clinically. We have also observed one patient with myxedema whose peak furosemide level and total absorption were less than when he was treated with replacement doses of thyroid hormone. Following treatment, he was also much less edematous. Of the pharmacological agents that can attenuate the action of diuretics, nonsteroidal antiinflammatory agents are by far the most important.h7 These agents not only shift the sodium excretion versus serum furosemide concentration curve to the right, but also shift the sodium excretion rate versus urinary furosemide excretion rate to the right as well. In addition, peak sodium excretion per serum furosemide level and urine sodium excretion per furosemide excretion rates are lower than under control circumstanceshx Thus, there is probably inhibition of furosemide secretion and a counteracting of furosemide’s tubular action as well. These probably occur because loop-acting diuretics cause vasodilation of the afferent renal arterioles secondary to the release of prostaglandins. Nonsteroidal agents block this vascular effect.7y-x1There is also evidence that they cause enhanced sodium chloride reabsorption (probably in the loop of Henle), perhaps by preventing the release of prostaglandins and their subsequent action of impairing sodium chloride reabsorption in the thick ascending limb.x’ Of interest, there has been recent evidence that nonsteroidals also enhance loop reabsorption during thiazide diuresis in rats, partially blunting the thiazide diuresisS3 Whether such a

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mechanism opposing thiazide action occurs in man is under debate. The nonsteroidal agents also inhibit renin release, possibly leading to increased risk of hyperkalemia when potassiumsparing diuretics are used.“’ Probenecid inhibits proximal tubular secretion of loop agents as well as that of the thiazides. The diuretic is delivered more slowly to its tubular site of action, resulting in prolonged periods in which the diuretic level in the tubular lumen is at its maximally effective excretion level. From the latter, it can be argued that smaller, frequent oral or intravenous doses or a continuous drip of diuretic would be more efficient in causing a diuresis than would large boluses of diuretic that would lead to large but inefficient excretion rates. Thus, both pharmacokinetics and pharmacodynamics are important in determining response to a diuretic or a given dose of diuretic. CLINICAL USE OF DIURETICS Hypertension

Diuretics have long been considered the firstline drug for the treatment of primary hypertension. Despite their usefulness, such a position needs to be modified because of advances in our understanding of primary hypertension and the emergence of new antihypertensive drugs. Several arguments can be advanced against the indiscriminate universal consideration of diuretics as first-line drugs in primary hypertension. Diuretics do not satisfy the most important criterion for an ideal antihypertensive, namely to correct the important abnormalities of primary hypertension without inducing new abnormalities capable of interfering with the well being of the recipient. Primary hypertension occurs in a heterogeneous group of patients who can be differentiated into several subgroups by various hormonal, clinical, and hemodynamic characteristics. It is intuitively clear that a heterogeneous group of hypertensive subjects cannot be treated homogeneously by a single drug. Although diuretics are successful in correcting the elevated arterial pressure in many hypertensive subjects, thus lowering atherosclerotic risk, they induce metabolic changes (hyperlipidemia, see following section) that may increase

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the risk of atherosclerotic vascular disease. The balance of these opposite effects may be to leave the atherosclerotic process unaffected as evidenced by the failure of diuretic therapy to lower the incidence of coronary artery disease. Diuretics fail to reverse some of the end organ damage induced by hypertension, notably left ventricular hypertrophy. In addition to their failure in correcting the abnormalities of primary hypertension, diuretics induce several hormonal abnormalities that may limit their antihypertensive effectiveness and increase their side effects (hyperreninemia and secondary hyperaldosteronism). Mechanism of Antihypeflensive Effect Despite intense investigation, the exact mechanism of the antihypertensive effect of diuretics is not completely understood. What is certain is that a certain degree of negative salt balance and maintained volume contraction are essential for the antihypertensive effect. This is evidenced by the observation of Tarazi and his colleagues84 of a reduced plasma volume during chronic diuretic therapy and the common clinical observation of loss of antihypertensive effect with increased salt intake. The chronic hemodynamic effects consist of normal cardiac output and some normalization of systemic vascular resistance.“” The antihypertensive effect of diuretics is limited by the hyperreninemia that they induce and the secondary hyperaldosteronism. The former leads to the generation of higher levels of the vascoconstrictor angiotensin II, and the latter enhances sodium reabsorption in the cortical collecting tubule and reduces the natriuretic efficiency of these drugsx6 The secondary changes are of importance in the choice of additional drugs if the antihypertensive effect is inadequate and better control is sought. The additional drugs should preferably have suppression of elevated levels of angiotensin II as part of their antihypertensive effect (vide infra).x7 Monotherapy If diuretics are chosen as initial therapy for a patient with primary hypertension, thiazides are the preferred category of diuretics because of their longer duration of action, simple regimen, proven clinical efficacy, and cost.8X It is presently recognized that smaller doses of thiazides

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are adequate in a large proportion of patients, and the physician should start with the smallest dose.89 Furthermore, increasing the dose beyond a certain level only increases the side effects of diuretics, with little gain in antihypertensive effect.90-92 This is particularly true of chlorthalidone, which is notorious for a very steep-dose side effect and flat-dose antihypertensive-effect profile. It should be noted that in patients whose hypertension is not well controlled with a diuretic, the subsequent approach need not be one of additional drugs but can be one of substitution. This illustrates a new general approach in antihypertensive therapy that aims to limit the tendency for piling up antihypertensive drugs and asks the physician to carefully examine the patient’s profile and select rational designed therapy instead of indiscriminate step-care therapy. Combination

Therapy

The decision to use diuretics in combination with other agents invites the physician to consider the complimentary properties of the drugs to be combined. As noted previously, if the patient is already on diuretics, then a useful approach is to use drugs with a mechanism of action that is additive to the diuretics. Converting enzyme inhibitors will correct the secondary hyperreninemia and hyperaldosteronism of diuretic therapy and thus will not only potentiate the antihypertensive effect, but will also limit the side effect of hypokalemia.87,93.94 It should be noted that the antihypertensive effectiveness of converting enzyme inhibitors is greatly enhanced in a patient receiving diuretic therapy, and thus caution and small doses are recommended. Alternatively, p-blockers can be used to control the hyperreninemia and have the additional quality of lowering blood pressure by non-renin-mediated mechanisms. Diuretics need to be an essential part of any regimen containing vasodilators such as hydralazine or minoxidil. Diuretics are so flexible in the antihypertensive armamentarium that they can be combined with almost any other antihypertensive with additive effects. Secondary Hypertension Corticosteroid

antihypertensive

Diuretics are effective agents in states of corticoste-

excess.

roid excess: primary aldosteronism, Cushing’s disease, iatrogenic corticosteroid excess, and hypertension associated with the use of contraceptive pills. In primary aldosteronism, spironolactone has been advocated as specific therapy because of its antialdosterone properties. The antihypertensive effect of spironolactone therapy is directly related to the induction of a negative sodium balance. Furthermore, other diuretics acting at the level of the cortical collecting tubule (amiloride and triamterene) are as effective as spironolactone in controlling the blood pressure and correcting the hypokalemia or primary aldosteronism. In primary aldosteronism due to an adrenal adenoma, the ideal treatment is resection of the tumor. Diuretic therapy is used in this case to control the blood pressure and correct the negative potassium balance to reduce the rate of operative complications due to hypokalemia. In primary aldosteronism due to bilateral adrenal hyperplasia, surgery is neither curative nor indicated, and diuretics are the mainstay of therapy. There is no advantage to spironolactone over other potassium-sparing diuretics. In fact, because of the annoying side effects of gynecomastia and breast tenderness with spironolactone, the other diuretics may be preferable. Diuretics should be used in sufficient doses to induce a negative sodium balance and correct the hypokalemia. To achieve the former, the addition of a thiazide diuretic may be needed. Renal parenchymal disease. The hypertension associated with renal parenchymal disease is frequently characterized by salt retention and an increase in extracellular fluid volume that can exist even in the absence of overt vascular congestion or edema. Some forms of renal parenchymal disease may also be associated with an increase in renin secretion (Page kidney). This condition is easily recognized when the plasma renin levels are elevated. When plasma renin levels are ‘normal” they need to be examined in the light of the state of the extracellular fluid volume. Such an analysis will frequently show that apparently normal levels are indeed abnormally high for the degree of volume expansion. The use of diuretics in renal failure requires attention to two important constraints: first, the effects of renal parenchymal disease on the pharmacokinetics and effective-

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ness of diuretics, and second, the effects of diuretics on renal function. The changes in pharmacokinetics have been discussed previously. Azotemia is a common complication of diuretic therapy for the hypertension of renal parenchymal disease because of the tendency to use diuretics to the exclusion of other drugs and the use of higher doses.(‘” The physician should attempt to balance the usefulness of diuretics against the observed decline in renal function. Blood pressure can be controlled without the cost of severe azotemia if one uses diuretics as part of a balanced regimen. Furthermore, the use of other antihypertensives may be beneficial. If one considers that glomerular hypertension may be a major factor in the progression of renal disease, then reduction of glomerular pressures may prove useful in delaying the inevitable demise of nephrons. There is experimental and clinical evidence that suggests that converting enzyme inhibitors may reduce the rate of nephron loss. y5-yxThis finding, if confirmed in large randomized clinical studies, will have a great impact on the design of therapeutic regimens in patients with hypertension secondary to renal parenchymal disease. However, converting enzyme inhibitors may precipitate hyperkalemia in patients with chronic renal disease. Congestive

Heart Failure

The use of diuretics in congestive heart failure is subject in its efficacy and complications to the severity of the disease and the urgency of therapeutic response. The indications and types of medications used are familiar enough not to warrant repetition. The elements that deserve highlighting as far as pharmacokinetic changes and renal responses have been discussed above. A frequent occurrence is the development of severe azotemia in decompensated congestive heart failure when rapid diuresis is effected leading to reduction in effective arterial volume while total extracellular fluid volume remains increased. This azotemia will be accompanied by diuretic resistance and frequently an attempt at overcoming this resistance by use of powerful diuretic combinations. A vicious circle is thus established. In such conditions withdrawal of diuretic therapy and maximization of alternate therapy (inotropy, after load reduction), will

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lead to resolution of the azotemia and reestablishment of diuretic responsiveness. Finally, it should be remembered that diuretic-treated patients with congestive heart failure arc at greater risk of developing complications with angiotensin-converting enzyme inhibitors? These can be avoided by use of small doses and slow titration. Edema of Renal Disease

Edema may be the first clue to the existence of renal disease and is observed in at least three major renal syndromes: nephrotic syndrome, nephritic syndrome, and renal failure. The cause of the edema varies among the syndromes, and so do the conditions governing the use of diuretics. However, of general importance for all these syndromes is to distinguish between renal indications for diuretic therapy and cosmetic reasons. The physician using diuretics in the context of renal disease should be aware of the particular vulnerability of these patients to the complications of therapy and should adhere to the primary principle of doing no harm. The mechanism of edema formation in the nephrotic syndrome is not completely understood. Several factors are involved, and their respective contributions may vary between different diseases and patients. The traditional view that hypoalbuminemia and the resulting decrease in plasma volume initiate the cascade of events leading to nephrotic edema has been challenged by several observations. The heterogeneity of patients and diseases precludes a unifying universal mechanism to explain salt retention. For operational reasons it is helpful to think of the edema as being of multifactorial origin and to approach it with attention paid to the different factors involved. The most effective therapy for nephrotic edema is obviously treatment of the glomerular disease. Measures that decrease or eliminate the proteinuria will curtail or clear the edema. Although this task is best left for the renal specialist, the internist caring for patients with nephrotic syndrome has at his or her disposal several interventions that can limit the edema and help in its resolution. Of primary importance is restriction of dietary sodium chloride. This prevents any further increase in the edema. In prescribing salt restriction it is useful to

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distinguish between the salt content and the sodium content of the diet (a diet with 1 gram Na has 43.5 mEq of Na and a diet with 1 gram salt has 17 mEq of Na). The degree of salt restriction needs to be balanced against the practicability of the prescribed diet, its palatability, the degree of edema, and the course of the disease. Reevaluation of dietary prescription should be as much an option to be considered as modification in pharmacological therapy. When strict sodium restriction is prescribed, particularly in the patient receiving diuretics, restriction of water intake should also be considered to avoid dilutional hyponatremia. The physician should carefully consider the indication for the use of diuretic therapy in the nephrotic patient. The medical indications include anasarca, or the presence of pulmonary, cardiovascular, or skin complications. Cosmetic reasons may be of importance to some patients who are intolerant of the distortion of body image. The physician should attempt to limit the use of diuretics in the latter condition as much as possible. It should be remembered that diuretic therapy in the nephrotic syndrome is palliative, and therefore the need for it should be considered in conjunction with the course of the renal disease. Rapid initiation of diuresis is indicated only under very special circumstances where life-threatening complications of salt retention are at hand. In most patients, a deliberate and slow titration of diuretic dosing is satisfactory. The most common causes for refractoriness of nephrotic edema remain to be lack of compliance with dietary and pharmacologic prescription and appropriate use of diuretics. In addition, in severely hypoalbuminemic patients, severe contraction of effective arterial volume and renal underperfusion can lead to renal unresponsiveness. In severely edematous and hypoalbuminemic patients, use of albumin infusions and volume expanders have been advocated. Albumin infusions are costly, rapidly wasted in the urine, and of transient benefit. Their use should be restricted to patients with severe hypoalbuminemia, prerenal azotemia, and renal failure. In many of these, albumin infusion may restore the responsiveness to diuretics. Reversal of acute renal failure has been described in some patients who presumably

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develop renal parenchymal edema secondary to severe hypoalbuminemia. In patients with chronic renal insufficiency, the maintenance of salt balance is dependent on the degree of renal impairment and amount of salt in the diet. In most patients with moderate and stable renal insufficiency, balance can be easily maintained within the limits of usual salt intake. Nevertheless, the most common reason to use diuretics in patients with renal impairment is the enhancement of urinary sodium excretion in the following settings: coexistent hypertension, nephrotic edema or congestive heart failure, severe renal failure when sodium intake exceeds the ability of the kidneys to excrete the salt load, and edema of any reason. The use of diuretics in renal failure should adhere to the following principles. Potassiumsparing diuretics should be avoided because in the setting of renal failure potassium balance is crucially dependent on potassium secretion in the cortical collecting tubule. Carbonic anhydrase inhibitors should be avoided because they exacerbate the acidosis of renal failure. Thiazides can be used until GFR decreases to approximately 30 mL/min. Two factors dictate this limitation: first, with progressive renal failure, endogenous acids compete with thiazides for secretion in the proximal tubule, thus access of thiazides to their luminal site of action is reduced: second, thiazides and chlorthalidone have a flat dose response curve and low potenCY.h3The thiazide-like diuretic, metolazone, retains a natriuretic effect even in the face of advanced renal insufficiency.“” Loop diuretics become the mainstay of diuretic therapy at GFRs of 30 mL/min or less. When patients are resistant to loop diuretics, or when the diuresis is not adequate for the clinical state, combination therapy is in order. The usual combinations include loop diuretics and thiazides or loop diuretics and metolazone.57.10” In addition to enhancement of sodium excretion, diuretics are used in patients with renal insufficiency with special complicating problems such as hyperkalemic distal renal tubular acidosis. Two complications are of particular importance in the setting of renal failure: reduction in GFR and increased risk of extrarenal toxicity. Reduction in plasma volume leads to some diminution in GFR at all levels of renal function. In patients

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with underlying renal failure, this reduction may have disastrous consequences. Therefore, monitoring of renal function is mandated during initiation of diuresis, change in diuretic regimen, or intercurrent illnesses that may affect salt balance. A balance between adequate diuresis and compromise in renal filtration should be carefully achieved. Extrarenal toxicity is increased in the setting of renal failure because of the need to use high doses. Ototoxicity is the most important side effect. Most loop diuretics are capable of inducing neurosensory hearing loss that may be irreversible, and although the incidence might be higher with some loop diuretics, it should be remembered that all are capable of causing the damage (see following section). Edema of Hepatic

Disease

The role of diuretics in the management of ascites from liver disease is a recurring topic for controversy. The evidence suggests that in patients with early and modest ascites, salt restriction and use of mild diuretics (spironolactone or amiloride) is frequently successful. The difficulty, and consequently the controversy, occurs when patients with more severe disease fail to respond to conventional therapy. In this setting the use of large doses of loop diuretics and/or combination diuretic therapy has been associated with untoward complications.10’-105 Considering the fact that the rate of mobilization of sequestered ascitic fluid is small, brisk diuresis will frequently reduce effective arterial volume and precipitate azotemia. Conceptually, it is more rational to attempt to reduce accumulation of fluid in a defined relatively sequestered space more directly by paracentesis. When adequate attention is paid to the preservation of intravascular volume (albumin infusion), large volume paracentesis is effective and safe.“‘” Interestingly, alleviation of a tense ascites by paracentesis is often associated with improved responsiveness to diuretics. The latter will continue to play a role in the prevention of reaccumulation. Diuretic resistance is frequently observed in the hepatorenal syndrome. The intense renal vasoconstriction that is the hallmark of the disease is the main reason for reduced response and underlies the sodium avidity of the syn-

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drome. Renal vasodilation with dopamine may in some patients restore diuretic responsiveness IlKi Prevention

of Renal Failure

Contrast-Induced

Acute Renal Failure

Prevention of contrast-induced renal failure is based on the principal of maintaining adequate renal perfusion and enhancing excretion of the offending agent in a diluted form to minimize renal toxicity. This principle stems from a consideration of the factors that predispose to renal failure with administration of dye, namely reduced renal perfusion and amount of contrast used. Diuretics alone are not useful in this setting because, although they increase urinary flow, they may induce volume contraction and lead to a reduction in renal perfusion. Hence, diuretics should only be used in conjunction with maintained volume expansion before, during, and after the administration of a dye load.io7JUX Mannitol is particularly useful in this setting because of its volume expansive properties, rapidity of effect, and ease of titration.109J1” Acute U-ate Nephropathy

Acute urate nephropathy occurs in the setting of large uric acid loads released from endogenous sources, commonly during initial chemotherapy of hematologic malignancies. Renal protective measures are aimed at reducing the crystallization potential of uric acid and enhancing its renal clearance. Both purposes can be achieved by maintaining high flows of an alkaline urine.“‘J” The idea1 method to achieve this goal is volume expansion with administration of alkali.“” Diuretics are used as adjunctive measures in patients in whom, for any reason, volume expansion with alkali does not elicit a satisfactory diuresis or who cannot tolerate the amount of fluid expansion required by alkali therapy. Disorder

of Calcium

Metabolism

Nephrolithiasis

A role for thiazides in the treatment of nephrolithiasis can be construed from their known chronic effects on urinary calcium excretion. Thiazides enhance calcium reabsorption in

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the distal convoluted tubules114 and in membranes serving as models for the distal nephron, such as the urinary bladder of the turtle and flounder. Furthermore, diuretic-induced volume contraction enhances proximal calcium reabsorption. Metolazone and indapamide work by mechanisms similar to thiazides.li5Jr6 In contrast, loop diuretics, carbonic anhydrase inhibitors, and osmotic diuretics have no role in the treatment of nephrolithiasis because all of these compounds increase calcium excretion. Diuretics are expected to be effective in categories of stone disease where urinary calcium excretion is thought to play a role. These categories are hypercalciuria and hypercalciuria combined with uricosuria or hyperoxaluria.“’ They may also be useful in patients who do not exhibit any metabolic abnormalities but continue to form stones. In some of these patients, a deficiency of urinary crystallization inhibitors has been identified, and the normal levels of urinary calcium excretion may be inappropriately high for the activity of these inhibitors. Hypercalcemia

Diuretics that find no use in nephrolithiasis are ideal for the treatment of hypercalcemia. Loop diuretics, by virtue of their site of action, inhibit calcium reabsorption in the loop of Henle and increase urinary calcium excretion.118J1y This effect can be dampened by enhanced proximal reabsorption if volume depletion occurs.‘?” The way to maximize the effect of loop diuretics is to couple their use with administration of saline and continuous replacement of urinary losses of sodium and potassium.‘“’ Disorders

of Water

Metabolism

balance and extracellular volume contraction be maintained. This will enhance sodium reabsorption in the proximal segments and reduce GFR, thus leading to diminished urine volume. This crucial dependence on a contracted extracellular volume explains why the therapy is potentiated by sodium restriction and thwarted by excess sodium intake. Thiazide diuretics are the agents commonly used. In one form of nephrogenie diabetes insipidus, namely the one associated with chronic lithium therapy,‘” the use of diuretics must be coupled with monitoring blood lithium levels. Conditions for enhanced sodium reabsorption are associated with reduced renal clearance of lithium and may lead to lithium intoxication. Amiloride has been shown to be effective in reducing the polyuria of lithium nephrotoxicity and may be associated with less risk of lithium toxicity.“’ Nevertheless, it is advisable to monitor lithium levels during the initiation of amiloride therapy and adjust the lithium dose accordingly. The success of diuretic therapy with some forms of nephrogenic diabetes insipidus should not be construed as a blanket recommendation for all forms of the disease, and if other abnormalities are present (hyperkalemia, acidosis), alternate therapy or nonthiazide diuretics (furosemide) may be used. Hypothalamic

Diabetes Insipidus

Diuretics have been used as adjunct therapy in patients with hypothalamic diabetes insipidus. The rationale for their use lies in inducing volume contraction that promotes proximal reabsorption and thus decreases distal fluid delivery and lowers urine volume. With greater ease of administration of vasopressin analogues, the need to use diuretic therapy is reduced if not abolished.

Nephrogenic Diabetes Insipidus

The use of diuretics to treat a condition that is characterized by high urine flow and an inability to concentrate the urine may appear paradoxical. The rationale for this seemingly dangerous therapy lies in the use of volume contraction induced by diuretics to enhance fluid concentration by segments of the nephron that are not affected by the disease, namely segments proximal to the collecting tubule.i2’ The crucial factor in the effectiveness of diuretics in this setting is that a negative sodium

Hypona tremia

Hyponatremia is both a feared complication of diuretic therapyi23,i’4 and, in certain settings, an indication for their use. A careful evaluation of the cause of hyponatremia should precede the effort to correct it. The rationale of using loop diuretics in this setting is to effect loss of hyponatric urine while replacing with isonatric solutions, or as the case may be, hypertonic saline solutions. The correction of hyponatremia can proceed at a rate of 1 to 2 mEq/h: that

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is generally considered to be safe as long as the correction is limited to achieve mild hyponatremic levels and complete correction is not achieved acute1y.l” Miscellaneous Cerebral Edema

Mannitol is the celebrated agent used in this setting. Its salutary effect is due less to its diuretic effect than to its osmotic effect, since the edema it is used to treat is not dependent on total body water but rather on excess water in the confines of the cranium. The effects of mannitol can be dramatic and life saving, but its use should always be coupled with judicial management of fluid volume.12h Mannitol is used to reverse acute episodes and is less useful chronically.“’ Indeed, prolonged use has been associated with acute renal failure. Steroids and treatment of the underlying disease need to supplement and supplant the use of mannitol. Reduction of Total Body Bicarbonate Stores

Most forms of metabolic alkalosis are either mild or, if severe, of a short duration, and they are readily correctable by reversing the predisposing condition. Therefore, the need to reduce total body bicarbonate stores is rare. If the alkalosis is severe and life threatening, the alkali excess can be reduced by administration of an acid solution, such as arginine-HCI. Diuretics may be used in cases of sustained metabolic alkalosis in patients with pulmonary compromise, in whom the alkalotic pH unfavorably affects oxygen dissociation kinetics. In this setting, carbonic anhydrase inhibitors are useful, and the reduction in bicarbonate stores is salutary. Urinary Alkalinization

Therapeutic urinary alkalinization is used to enhance urinary excretion of potential toxins, to prevent crystallization in cases of uric acid excess, and to reduce renal injury from amphotericin B. The only group of diuretics useful in this setting are the carbonic anhydrase inhibitors and only for a short duration of time. With prolonged use, a metabolic acidosis develops and urinary alkalinization is replaced by enhanced distal acidification. Loop diuretics are

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not useful when used alone because they lead to an enhancement of hydrogen ion secretion in the collecting tubule and thus lead to lowering of urine pH. The most effective form of urinary alkalinization remains the administration of alkali, and diuretics can be used as an adjunct in patients who cannot handle a sodium load. Hypevhosphatemia

Most of plasma phosphate is ultrafiltrable, and 3% to 20% of the filtered load is excreted in the urine. Seventy percent to 80% of phosphate reabsorption occurs in the proximal convoluted tubule, the rest is reabsorbed in the distal and collecting tubules. Proximal reabsorption is dependent on sodium reabsorption, pH, and parathyroid hormone. Carbonic anhydrase inhibitors are the most potent phosphaturic agents. Little phosphaturia occurs with osmotic diuretics, and no clinically significant effect is observed with Na channel blockers or aldosterone antagonists. Treatment of hyperphosphatemia may be necessary when the condition develops from acute load secondary to chemotherapy, rhabdomyolysis and phosphate laxative abuse, or when urinary phosphate excretion is diminished, such as a reduced GFR and hypoparathyroidism. If renal function is still adequate, phosphate levels can be reduced by infusing saline, bicarbonate, and carbonic anhydrase inhibitors. If renal function is inadequate, dialysis may be used to lower phosphate levels acutely, and phosphate binders can be used to prevent chronic hyperphosphatemia. CLINICAL

TOXICITY

A variety of side effects have been encountered with diuretic therapy. The severity of these effects is closely dependent in most cases on the dose and potency of the diuretic in use. Certainly, the nature of the underlying disease under treatment also contributes to the occurrence or relevance of these side effects. Some of these effects are serious and life threatening whereas others are relevant to patient welfare only in certain subjects.

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Hypokalemia Etiology

With the exception of sodium channel blockers and aldosterone antagonists, most diuretics induce a decrease in plasma potassium levels with chronic treatment.12sJ29 The degree of reduction is dependent on several factors including the dose and pharmacokinetics of the diuretic, the use of combined diuretic therapy, and the intake of sodium, potassium, and other drugs. The mechanisms of induction of hypokalemia are multiple, and some are shared by most diuretics whereas others are specific to the class of agents depending on their site of action. These mechanisms often work synergistically to promote urinary potassium loss. The major common mechanism is the increase in distal flow and delivery of sodium because of inhibition of reabsorption in segments proximal to the cortical collecting tubule,rJO the major site of potassium secretion. This mechanism is enhanced by the secondary hyperaldosteronism that occurs with chronic diuretic therapy. High levels of aldosterone are known to enhance Na-K-ATPase activity in the cortical collecting tubule and to increase luminal sodium entry. Both of these effects contribute to the generation of a transepithelial potential with a negative lumen and thus create a favorable electrical gradient for potassium secretion. Furthermore, aldosterone increases the potassium conductance of the luminal membrane, thereby facilitating the exit of potassium down its electrochemical gradient. A mechanism peculiar to loop diuretics is inhibition of potassium reabsorption in the thick ascending limb of Henle loop, where potassium is reabsorbed by a common transporter with sodium and chloride (vide supra). Diuretics acting at the level of the proximal tubule and osmotic diuretics can also decrease the amount of potassium reabsorbed proximally and lead to an increase in distal delivery of potassium and increase the degree of potassium loss. When diuretics are used in combination, many of the above mechanisms are magnified and the kaliuretic consequence can be detrimental to the patient’s welfare and survival. Because increased distal delivery of sodium is a major factor in the kaliuresis induced by diuretics, increases in sodium intake

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that will further potentiate this effect will almost certainly worsen the hypokalemia. Risks

A decrease in potassium level during diuretic therapy is almost a universal finding, and in many individuals the decrease occurs within the normal range with no untoward consequences. It is only when frank hypokalemia occurs that increased risk is encountered and only in particular patient populations. Hypokalemia has general nonspecific effects such as muscle weakness that may interfere with the patient’s well being and decrease his or her compliance with the drug. The more serious risks of hypokalemia relate to cardiovascular and metabolic consequences. Cardiovascular consequences. Many studies have proposed to prove an increased risk of sudden cardiac death and fatal arrhythmias in hypokalemic subjects.‘31-‘33 An equal number of studies have attempted to refute these assertions of nefarious effects of hypokalemia.‘3”-‘3h This lack of consensus in published studies is likely due to heterogeneous populations. varying degrees of hypokalemia. and different methods used to detect cardiac consequences. What can be gleaned from this sea of controversy and recommended to the practicing physician is that in patients who are at high risk of developing serious cardiac arrhythmias because of underlying myocardial disease or treatment with digitalis preparations, hypokalemia should be avoided and, when detected, corrected. Again, this recommendation holds for frank hypokalemia and not decreases in potassium levels within the normal range. Safe and effective ways for correction of hypokalemia are described later. Another cardiovascular consequence of hypokalemia that is not as commonly appreciated is that low potassium levels blunt the antihypertensive effects of diuretic therapy. Potassium repletion has been observed to improve blood pressure control.r37 However, this effect may not be due solely to the correction of hypokalemia and the reversal of vascular effects but also to the natriuretic effects of potassium supplementation. Metabolic consequences. The major metabolic concern with hypokalemia is the induction

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of glucose intolerance. Although this is of little consequence in the otherwise healthy individual, in diabetic patients this can be a factor in the precipitating loss of control.1”8.‘39 However, the situation is not uniformly simple. Many diabetics, particularly those with diabetic nephropathy, which constitutes a major proportion of diabetics requiring diuretics, have hyporeninemic hypoaldosteronism and are more prone to hyperkalemia. Another metabolic consequence of hypokalemia is the promoted development of metabolic alkalosis. Low circulating levels of potassium enhance the production of the urinary buffer ammonia. This is in conjunction with the hyperaldosteronism prevalent in diuretic-treated patients, which leads to the development of metabolic alkalosis.‘40 The severity of the alkalosis varies with the magnitude of the diuresis. Powerful diuretic combinations, such as a loop diuretic with thiazide or loop diuretics with metolazone, produce severe hypokalemia and severe metabolic alkalosis. Correction of the hypokalemia ameliorates the alkalosis, but does not completely reverse it. Prevention and Correction

Prevention of hypokalemia is readily achieved in many patients by attenuation of the factors that exacerbate potassium loss. Limitation of diuretic dose in conditions where higher doses have no therapeutic benefit is an important prevention modality. In hypertensive subjects, the maximal antihypertensive effect of thiazide and thiazide-like diuretics is achieved at a low dose.“O Further increases in dose lead to more severe hypokalemia with little enhancement of antihypertensive effect. Limitation of dietary salt intake is an important form of hypokalemia prevention. Urinary potassium losses can be greatly influenced by the amount of sodium delivery to the distal nephron, and exaggerated sodium intake not only thwarts the therapeutic benefits of diuretics but also exaggerates their side effects. Because of the achievement of steady state during chronic diuretic therapy, urinary sodium excretion as determined by a 24-hour collection is a good and reliable index of sodium intake. This test should be used in any patient who manifests therapeutic resis-

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tance to diuretics in conjunction with the development of side effects. Indication. The treatment of hypokalemia is indicated when the decrease in plasma potassium level is severe (less than 3 mEq/L), when the patient is concurrently receiving digitalis preparations, and when underlying cardiac disease predisposes the patient to serious arrhythmias.14’ In addition, patients who are symptomatic from the hypokalemia should also be treated. It should be stressed that the first step towards correction of the hypokalemia is reexamination of the dose of diuretics used and its appropriateness, followed by an assessment of the presence of factors that exacerbate the kaliuresis before undertaking other therapies. Approach. Rational therapy of hypokalemia is based on correcting the total body deficit of potassium by supplementation and reduction of losses. Potassium supplementation may be achieved by either increasing dietary potassium or prescribing potassium in liquid or tablet preparations.r4’,r4’ An important drawback of increasing dietary potassium is the simultaneous increase in caloric intake. Many potassium-containing preparations are available and are presented in Table 3. Combining kaliopenic and kaliuretic diuretics and using converting enzyme inhibitors are two methods to decrease potassium loss. Each of the methods interferes with one of the mechanisms originally leading to kaliuresis. Amiloride and triamterene block sodium channels in the luminal membrane of the cortical collecting tubule, thereby preventing the creation of the favorable electrical gradient that promotes potassium secretion.lj” Angiotensin-converting enzyme inhibitors blunt the secondary hyperaldosteronism of diuretic therapy and remove the kaliuretic influence of aldosterone.R7 Both mechanisms have proved to be effective, and the choice of which modality to use depends on the particular patient and the consideration of the additional effects of the drugs. If additional diuresis is required, kaliferic diuretics are chosen. Converting enzyme inhibitors are particularly useful in the patient with congestive heart failure who requires afterload reduction and, because of their additional hypotensive effect, in the hypertensive patient who is not well controlled by diuretics alone. However, this property limits their use in hy-

DIURETIC

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THERAPY

Table Dosage Powder Potassium

Form

Effervescent Potassium

Formulation

Manufacturer

Strength (mEq1

Abbott Forest

20 20

26.49

Bristol

25

27.29

Rapid

Bristol Bristol

25 50

27.29

Not effective

39.39

metabolic

Comments

Cost’

25.00

tablets chloride Cl

absorption,

good

bioavailability

bicarbonate

K-Lyte K-Lyte Solid preparations Slow K

Ciba

K-tab Klotrix

Abbon

Micro-K K-Dur K-10

Robins

“Calculated

Potassium

chloride

K-LOR K-CIEL

K-Lyte Potassium

3. Oral

a 10 10

Kev Atra for 1 tablet

8 20 10

8.59 10.09 9.49 8.19 13.79 10.25

in presence

of Cl-deficiency

of

alkalosis

Sugar coated, wax matrix Film coated, wax matrix Film coated, wax Microencapsulated Immediately Immediately

matrix

dispensing dispensing

per day for 1 month.

potensive patients. Both modalities should not be used indiscriminately in the patient with reduced renal function or together, as hyperkalemia can develop. Hyponatremia

Although observed relatively infrequently in patients taking diuretics, hyponatremia is no less serious. Indeed there have been reports of severe chronic diuretic-induced hyponatremia leading to irreversible brain damage.12sJ45-‘47 Hyponatremia is particularly problematic in patients taking diuretics that work in the diluting segments of the nephron. Three mechanisms are thought to contribute in various degrees to the development of hyponatremia. First, diuretics active in the cortical thick ascending limb of Henle impair the generation of dilute urine by blocking sodium reabsorption.14x Thus a limit is set on the amount of solute-free urine that the kidney can excrete. In other terms free water clearance is decreased. If the patient ingests free water faster than the ascending limb can generate it, hyponatremia is certain to follow. Second, volume contraction induced by diuretic therapy may increase the release of vasopressin into the circulation and thus lead to increased reabsorption of free water in the collecting tubule contributing further to the development of hyponatremia.1491’50 In addition, volume contraction enhances proximal reabsorption and limits solute delivery to the ascending

loop of Henle, a necessary requirement for urinary dilution. This mechanism may be particularly important in disease conditions that also activate such mechanisms as in patients with congestive heart failure.151.15’ Third, hypokalemia has been proposed as contributing to hyponatremia by facilitating sodium entry to cells. However, this mechanism has not been clearly defined, and although possible, does not seem to be of major importance. Lipid Changes

Significant increases in triglycerides and in low-density lipoprotein cholesterol are observed with most diuretics, but the clinical significance of this remains controversial. Increases in serum cholesterol with the administration of thiazides had been noted as early as 1964,15” but several more recent trials1s4-‘sh demonstrated this effect to be transient. In studies showing a sustained hypercholesterolemic effect, the difference between diuretic and control groups averaged only .09 to .19 mmol/L.“’ However, the finding by the Lipid Research Clinics Coronary Primary Prevention Trial demonstrating a 2% reduction in mortality for every 1% reduction in serum cholesterol,‘sx may indicate that even small increases in cholesterol are clinically significant. Because of their efficacy and low cost, diuretics should not and cannot be discarded solely on their predilection to increase serum cholesterol, but treatment should

240

MUJAIS,

be individualized used.

and the smallest effective dose

Hyperuricemia

Hyperuricemia is commonly observed in patients receiving diuretics. This is due to at least two mechanisms. First, many diuretics are organic acids that are secreted by the proximal tubules using the transport mechanism usually operative to secrete endogenous organic acids such as urate. Administration of diuretics thus decreases competitively the amount of uric acid secreted by the proximal nephron. Reduction of the dose of the diuretic may increase urinary urate excretion. Second, volume contraction enhances urate reabsorption in both the proximal as well as distal nephron segments.isy~‘“” Correction of volume contraction increases urinary urate clearance. The hyperuricemia of diuretic therapy is rarely severe and in most subjects remains asymptomatic. It may be of significance in patients with gout and requires correction in this setting. Reduction of diuretic dose or correction of volume contraction, although effective, may not be desirable in the patient with avid salt retention. The use of the uricosuric agent probenicid is contraindicated because it prevents access of the diuretics to their site of action, and diuretic response is blunted. Allopurinol can be used but only when there is a definite therapeutic indication, such as in the patient with gouty arthritis. Magnesium

Deficiency

Thiazides and loop diuretics increase the excretion of magnesium in proportion to their natriuretic potency. i6i Hypomagnesemia does develop in some patients with chronic diuretic therapy and may be a factor in the development of hypokalemia. I(,2 Failure to correct the hypomagnesemia may be associated with difficulty in correcting potassium depletion.ih’ The hypomagnesemia can be corrected by simultaneous limitation of dietary sodium and an increase in magnesium intake, except in patients with azotemia in whom hypermagnesemia can occur with magnesium supplementation. Kaliferic di-

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uretics, amiloride and triamterene and spironolactone also have a magnesium-sparing effect and can correct diuretic-induced magnesium deficiency. Ototoxicity

Loop diuretics are the only type of diuretics known to cause damage to the ear, and of these, ethacrynic acid appears to be the most harmful.lh3~ih” Diuretic-induced ototoxicity occurs mainly when high doses of diuretics are used in patients with renal failure, or when the diuretic is given concomitantly with other ototoxic agents such as aminoglycosides. It is important to note that in all reported cases of furosemide ototoxicity, the recommended rate of intravenous administration (4 mgimin) was exceeded.‘” Sexual Dysfunction

Complaints of sexual dysfunction have been identified as a cause of withdrawal from diuretic treatment in large trials of antihypertensive therapy. The mechanisms may be related to impairment of vascular control by the metabolic changes induced by diuretics. Diuretic

Withdrawal

Although not specifically a manifestation of diuretic toxicity, withdrawal of these agents is associated with clinically significant effects and may be the major component of the entity called “idiopathic edema.” As described above, diuretics induce a series of compensatory natriferic mechanisms. Cessation of diuretic intake leaves these mechanisms unbalanced, and avid sodium retention occurs to the point of inducing edema. In subjects who use diuretics to control body weight for esthetic reasons or professional needs (horse jockeys, models, etc), withdrawal of the drugs and its associated edema prompts reuse and a cycle of edema and diuretic abuse ensues.‘hS-1h7These subjects often present either with the puzzling complaint of cyclic edema or with a pseudo-Bartter’s syndrome. Eliciting a history of diuretic abuse is often difficult, and diagnosis may require testing for diuretic metabolites in the urine.

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Principles and clinical uses of diuretic therapy.

Principles and Clinical Salim K. Mujais, Uses of Diuretic Nancy A. Nora, and Murray NDUCTION OF diuresis as a therapeutic modality has long been a...
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