Metabolic Complications Associated With Use of Diuretics

Metabolic Complications Associated With Use of Diuretics Biff F. Palmer, MD Summary: Diuretics are commonly used therapeutic agents that act to inhibit sodium transport systems along the length of the renal tubule. The most effective diuretics are inhibitors of sodium chloride transport in the thick ascending limb of Henle. Loop diuretics mobilize large amounts of sodium chloride and water and produce a copious diuresis with a sharp reduction of extracellular fluid volume. As the site of action of diuretics moves downstream (thiazide and potassium-sparing diuretics), their effectiveness declines because the transport systems they inhibit have low transport capacity. Depending on the site of action diuretics can influence the renal handling of electrolyte-free water, calcium, potassium, protons, sodium bicarbonate, and uric acid. As a result, electrolyte and acid-base disorders commonly accompany diuretic use. Glucose and lipid abnormalities also can occur, particularly with the use of thiazide diuretics. This review focuses on the biochemical complications associated with the use of diuretics. The development of these complications can be minimized with careful monitoring, dosage adjustment, and replacement of electrolyte losses. Semin Nephrol 31:542-552 © 2011 Elsevier Inc. All rights reserved. Keywords: Furosemide, thiazide, diuretics, hypokalemia, metabolic alkalosis, hyperkalemia

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iuretics are widely used therapeutic agents and are generally safe but similar to any drug they may cause side effects. The metabolic disturbances associated with diuretics largely reflect an exaggeration of the physiologic effect of these drugs based on their site of action within the kidney. If the goal of diuretic therapy is to augment sodium excretion, then the consequences of successful natriuresis and of changes of other renal and extrarenal transport mechanisms must be fully appreciated so as to forestall complications. This review focuses on the fluid and electrolyte disturbances associated with the use of diuretics. Hyponatremia as a complication of diuretic therapy is discussed elsewhere in this issue.

DISORDERS OF SERUM POTASSIUM Disturbances in the serum potassium (K⫹) concentration are some of the most common metabolic side effects associated with the use of diuretics. Drugs that act proximal to the collecting duct are associated with hypokalemia. The development of hypokalemia is primarily the result of diuretic-induced changes in extracellular fluid volume, mineralocorticoid activity, and distal sodium delivery. These alterations lead to enhanced K⫹ excretion at sites distal to where the drug exerts its diuretic effect. Diuretics that act at the level of the collecting duct are associated with hyperkalemia and commonly are referred to as K⫹-sparing diuretics. These agents predispose to the Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX. Address reprint requests to Biff F. Palmer, MD, Professor of Internal Medicine, Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390. E-mail: [email protected] 0270-9295/ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2011.09.009

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development of hyperkalemia by disturbing K⫹ transport mechanisms localized in the collecting duct. The direct and indirect mechanisms by which diuretics disturb normal K⫹ homeostasis is discovered in the following paragraphs. The clinical consequences of these disturbances also are discussed. Hypokalemia Direct Tubular Effects of Diuretics

Diuretics that are associated with the development of hypokalemia exert effects on K⫹ transport mechanisms that are located at the drug’s tubular site of action. Overall, these effects tend to be of lesser importance in the generation of hypokalemia as compared with secondary changes, which are discussed later. Osmotic Diuretics. Osmotic diuretics are filtered by the glomerulus and then undergo little to no reabsorption by the tubules. These agents disrupt the osmotic gradient, which favors fluid reabsorption in the proximal tubule and as a result inhibit fluid reabsorption in this segment. Decreased fluid transport leads to a decrease in the luminal Na⫹ concentration and creates an unfavorable diffusion gradient for Na⫹ reabsorption. As a result, there is a sharp increase in delivery of Na⫹ and water to downstream nephron segments. Because filtered K⫹ is isotonically reabsorbed in the proximal nephron in rough proportion to bulk fluid transport, inhibition of fluid transport results in a proportionately similar reduction in K⫹ reabsorption. As a result, there is increased delivery of K⫹ to the distal nephron. Osmotic diuretics also disrupt the countercurrent exchange and urinary concentrating mechanism. As a consequence, these agents also may interfere with the medullary recycling of K⫹. Carbonic Anhydrase Inhibitors. Carbonic anhydrase inhibitors act primarily within the proximal tubule where they Seminars in Nephrology, Vol 31, No 6, November 2011, pp 542-552

Metabolic complications and diuretics

Figure 1. Under normal circumstances, increases or decreases in the effective arterial blood volume (EABV) result in reciprocal changes in distal Na⫹ delivery and circulating aldosterone levels such that renal K⫹ excretion is independent of volume changes. Administration of thiazide or loop diuretics causes each of these parameters to increase such that renal K⫹ excretion is enhanced and hypokalemia ensues.

inhibit luminal carbonic anhydrase. Because this enzyme plays a central role in proximal NaHCO3 reabsorption, these drugs markedly diminish acidification, Na⫹, and fluid reabsorption in this segment. Accompanying the decreased fluid reabsorption is a proportional decrease in the reabsorption of filtered K⫹. The net effect is increased delivery of NaHCO3, fluid, and K⫹ to the distal nephron. Loop Diuretics. The loop diuretics act within the lumen of

the thick ascending limb of Henle where they inhibit the electroneutral Na⫹-K⫹-2Cl⫺ cotransporter. As a result, delivery of NaCl and K⫹ to the distal nephron is increased. Thiazide Diuretics. The primary site of action of the thia-

zide diuretics is in the distal convoluted tubule. These drugs inhibit an electroneutral NaCl cotransporter located on the luminal surface.1 There is no direct effect of the thiazides on K⫹ transport in this segment. Rather, these agents are associated with increased renal K⫹ excretion through their effects to increase distal Na⫹ delivery in the setting of increased mineralocorticoid activity. Thiazide diuretics also possess the ability to inhibit carbonic anhydrase, particularly when administered in high doses.2 As a result, they may inhibit proximal K⫹ reabsorption in the same manner as more potent carbonic anhydrase inhibitors such as acetazolamide. Clinically, however, this proximal effect is of little significance. Secondary Effects of Diuretics

Although direct effects of diuretics on K⫹ transport mechanisms contribute to the development of hypokalemia, it is secondary effects induced by these drugs that account for the bulk of increased renal K⫹ excretion. The ability of these drugs to transform the normally inverse relationship between distal salt and water delivery and mineralocorticoid activity to one in which these parameters both increase is what underlies the kaliuretic effect (Fig. 1). To better understand

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these secondary effects a brief overview of renal K⫹ handling is provided. Potassium is freely filtered by the glomerulus. The bulk of filtered K⫹ is reabsorbed in the proximal tubule and loop of Henle such that only 10% of the filtered load reaches the distal nephron. In the proximal tubule K⫹ absorption is passive and is in rough proportion to Na⫹ and water. In the thick ascending limb of Henle, K⫹ reabsorption occurs via transport on the apical membrane Na⫹-K⫹-2Cl⫺ cotransporter. Secretion of K⫹ occurs in the distal nephron primarily in the initial collecting duct and the cortical collecting duct. Under most conditions, K⫹ delivery to the distal nephron remains small and is fairly constant. By contrast, the rate of K⫹ secretion by the distal nephron varies and is regulated according to physiologic needs. K⫹ secretion in the distal nephron is generally responsible for most of the urinary K⫹ excretion. The cell that is responsible for K⫹ secretion in the initial collecting duct and the cortical collecting duct is the principal cell. The cellular determinants of K⫹ secretion include the cell K⫹ concentration, luminal K⫹ concentration, potential (voltage) difference across the luminal membrane, and permeability of the luminal membrane for K⫹.3 Any condition that increases cellular K⫹ concentration, decreases luminal K⫹ concentration, or renders the lumen more electronegative will increase the rate of K⫹ secretion. In addition, any condition that increases the permeability of the luminal membrane for K⫹ will increase the rate of K⫹ secretion.4 All of the physiologic determinants of renal K⫹ secretion are found to affect one or more of the earlier-described cellular determinants of collecting tubule K⫹ secretion. Two of the most important physiologic determinants are mineralocorticoid activity and distal delivery of Na⫹ and water. Although increased distal delivery of Na⫹ and water and increased aldosterone activity can each stimulate renal K⫹ secretion, under normal physiologic conditions these two determinants are related inversely (Fig. 1). It is for this reason that K⫹ excretion is independent of volume status. For example, under conditions of a contracted extracellular fluid volume aldosterone levels increase. At the same time, proximal salt and water absorption increases, resulting in decreased distal delivery of Na⫹ and water. Renal K⫹ excretion remains fairly constant under these conditions because the stimulatory effect of increased aldosterone is counterbalanced by the reduced delivery of filtrate to the distal nephron. A similar situation occurs in the setting of expansion of the extracellular fluid volume. In this setting, distal delivery of filtrate is increased as a result of decreased proximal tubular fluid reabsorption. Under conditions of volume expansion the circulating aldosterone levels are decreased. The effect of the increased delivery of Na⫹ and water to stimulate K⫹ excretion is opposed by decreased circulating aldosterone levels such that renal K⫹ excretion again remains constant. Thus, there is a balanced reciprocal relationship between urinary flow rates and

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circulating aldosterone levels that serves to maintain K⫹ balance during normal volume regulation. Diuretic-induced hypokalemia is largely the result of disturbances in this relationship. Diuretics are potent stimulants of the renin-angiotensin-aldosterone cascade. The principal stimulant for renin release is diuretic-induced contraction of the extracellular fluid volume. Loop diuretics have an additional stimulatory effect on renin release through their ability to inhibit the Na⫹-K⫹-2Cl⫺ cotransporter at the level of the macula densa. In this segment, there is an inverse relationship between Cl⫺ reabsorption and renin release.5 By inhibiting Cl⫺ transport, loop diuretics enhance renin release. Once released, renin stimulates the formation of angiotensin II, which, in turn, stimulates the release of aldosterone from the adrenal gland. In the absence of diuretics, increased circulating levels of aldosterone induced by a contracted effective circulatory volume are not associated with a marked increase in renal K⫹ excretion. The kaliuretic effect is blunted because there is a simultaneous reduction in distal Na⫹ and fluid delivery as a result of enhanced reabsorption at nephron sites proximal to where aldosterone exerts its primary physiologic effect. In the setting of osmotic agents, carbonic anhydrase inhibitors, loop and thiazide diuretics, distal delivery of salt and water to aldosterone-responsive cells in the distal nephron is increased such that the kaliuretic effect of aldosterone is fully expressed. It is increased distal K⫹ secretion rather than decreased proximal K⫹ reabsorption, which accounts for the development of hypokalemia after the use of these diuretics. Characteristics of Diuretic-Induced Hypokalemia

The degree of hypokalemia associated with use of diuretics varies according to the agent used. In hypertensive patients taking thiazide diuretics, the serum K⫹ concentration decreases on average by 0.5 mEq/L. This decline can be as high as 0.9 mEq/L with use of the long-acting thiazide, chlorthalidone. Although loop diuretics are more potent natriuretic agents, they typically result in a milder degree of hypokalemia because the average decline in the serum K⫹ concentration is 0.3 mEq/L. This lesser effect may be related to the much shorter half-life of loop diuretics as compared with the thiazide diuretics. Although not proven, this smaller decline also may be related to the ability of loop diuretics to inhibit calcium absorption in the loop of Henle. The ensuing increase in calcium delivery to the lumen of the distal nephron may inhibit Na⫹ reabsorption and therefore diminish distal K⫹ secretion. The degree of diuretic-induced hypokalemia also is influenced by the amount of dietary Na⫹ intake. The administration of a diuretic in conjunction with the ingestion of large amounts of dietary Na⫹ (180-200 mEq/L) renders a patient particularly vulnerable to the development of hypokalemia.6 This particular combination allows for maximal Na⫹ and fluid delivery to the

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distal nephron at the very time aldosterone secretion is stimulated by the initial diuretic-induced contraction of extracellular fluid volume. On the other hand, extreme dietary Na⫹ restriction also tends to worsen the degree of hypokalemia associated with the use of diuretics.7 The basis for this effect is the curvilinear relationship between dietary Na⫹ intake and serum renin and aldosterone levels. This relationship is gradual at Na⫹ intakes of 80 mEq/L and higher. With Na⫹ intakes of 50 mEq/L and less, however, a steep increase in renin and aldosterone levels results. At these levels, the kaliuretic effect of aldosterone is the predominate factor in promoting renal K⫹ excretion. Sodium intake between these extremes (70-100 mEq/L) causes only a slight increase in aldosterone levels that when coupled with less delivery of Na⫹ to the distal nephron results in an overall decrease in renal K⫹ excretion. Thus, moderate dietary Na⫹ intake in hypertensive patients treated with diuretics will not only provide the maximal antihypertensive effect but also may limit the degree of K⫹ depletion. The decline in the serum K⫹ concentration usually develops within the first 2 weeks of therapy and then stabilizes as a new steady state is achieved. Thereafter, the serum K⫹ concentration should remain stable. Further declines in the serum K⫹ concentration are prevented by several factors that serve to decrease renal K⫹ secretion. Increased reabsorption of Na⫹ in the proximal nephron as a result of the diuretic-induced decreases in extracellular fluid volume serves to dampen Na⫹ and fluid delivery to the distal nephron. In addition, a progressive increase in mineralocorticoid activity is prevented because the development of hypokalemia tends to inhibit release of aldosterone from the adrenal gland. Chronic hypokalemia also is associated with a direct cellular effect leading to decreased distal nephron K⫹ excretion. Finally, K⫹ reabsorption is stimulated in the collecting duct under conditions of chronic hypokalemia as a result of increased activity of the H⫹-K⫹ adenosine triphosphatase (ATPase) pump.8 The development of more severe hypokalemia in the setting of chronic diuretic administration suggests some other perturbation in K⫹ balance such as an intercurrent illness leading to extrarenal K⫹ loss (diarrhea), a decrease in K⫹ intake (vomiting), or a change in diuretic dose. Although diuretics act to increase renal K⫹ excretion, isotopic measurements suggest that the decrease in the serum K⫹ concentration is greater than the decrease in total body K⫹ content.9 Long-term therapy of hypertensive patients with thiazide or loop diuretics is associated with an average decrease in the serum K⫹ of 15%. Measurement of total body K⫹ content has been shown to decrease on average by less than 5% and in some studies not at all. These observations suggest that a major component of diuretic-induced hypokalemia is mediated by a transcellular shift from the extracellular to the intracellular compartment. Factors that are associated with the use of diuretics and that may mediate this transcellular

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shift include increased circulating levels of catecholamines and aldosterone as well as the development of metabolic alkalosis. Consequences of Diuretic-Induced Hypokalemia

The most serious potential complication of diuretic-induced hypokalemia is the development of arrhythmias. This complication is particularly true for patients taking cardiac glycosides because the presence of hypokalemia can precipitate digitalis toxicity. A controversial issue has centered on whether diuretic-induced hypokalemia can give rise to fatal arrhythmias. In several large trials involving therapy of patients with mild hypertension, higher rates of cardiac mortality primarily manifesting as sudden death were noted among patients treated with high-dose diuretics who had baseline abnormal electrocardiograms.10 Diuretic-induced K⫹ or magnesium depletion leading to cardiac arrhythmias has been suggested as the mechanism underlying an increased risk for sudden death. In support, ventricular ectopic activity has been shown to increase over baseline in asymptomatic hypertensive patients who develop hypokalemia after the administration of diuretics. Case-control studies found that use of non– potassium-sparing diuretics were associated with an increased risk for sudden death.11 By contrast, other studies examining the treatment of hypertension in the elderly failed to show an increased risk for sudden death in patients despite the use of thiazide diuretic-based regimens.12-14 In these studies, however, lower doses of thiazides and in some cases a K⫹-sparing agent were used such that the tendency for development of hypokalemia was minimized. In summary, although a casual relationship has yet to be proven between diuretic-induced hypokalemia and the development of sudden death, the bulk of data strongly suggest the need for caution. Significant decreases in the serum K⫹ concentration should be prevented and when present K⫹ replacement should be initiated. Hypokalemia has two other effects that are potentially deleterious to the cardiovascular system. First, hypokalemia can increase blood pressure by a mean value of 5 to 7 mm Hg. This hypertensive response is reversible when oral K⫹ supplements are given to correct the diuretic-induced hypokalemia in patients on a constant diuretic dose.15 Second, hypokalemia has been linked to an increased incidence of strokes independent of other cardiovascular risk factors.16 Other complications of hypokalemia include the development of glucose intolerance and possibly disturbances in lipid metabolism. Prevention and Treatment of Diuretic-Induced Hypokalemia

The first approach to preventing diuretic-induced hypokalemia is to use the lowest dose of the drug possible (Table 1). With regard to thiazide diuretics, the majority of the blood pressure lowering effect is seen at doses of 12.5 to 25 mg/d. At higher doses, further blood pressure

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Table 1. Treatment and Prevention of Diuretic-Induced Hypokalemia Use low doses of the diuretic Moderate Na⫹ restriction (70-100 mEq/24 h) Correct magnesium deficit if present Oral K⫹ supplements (20-40 mEq/24 h) Combined therapy with an angiotensin-converting enzyme inhibitor, an angiotensin II–receptor antagonist, or a direct renin inhibitor Combined therapy with a K⫹-sparing diuretic

lowering is minimal, but rather metabolic side effects such as hypokalemia, hyperglycemia, and lipid abnormalities become more prevalent. Dietary manipulations also can be used in the prevention and treatment of diuretic-induced hypokalemia. As discussed earlier, overly strict dietary Na⫹ restriction as well as excess Na⫹ intake will tend to exacerbate renal K⫹ wasting. As a result, dietary Na⫹ should be restricted only moderately. If hypokalemia does develop, the patient can be tried initially on a diet of K⫹-rich foods. Although mild K⫹ deficits may correct with dietary manipulation, this approach is not generally effective for patients with more severe hypokalemia. In this setting, food intake in amounts sufficient to replenish a large K⫹ deficit would be complicated by excess caloric intake, potentially resulting in unwanted weight gain. A more feasible approach to the hypokalemic patient is to administer KCl supplements at doses of 20 to 40 mEq/d. Therapy is indicated particularly for patients taking cardiac glycosides and patients with underlying cardiac disease. In these high-risk patients even mild hypokalemia should be treated because more severe reductions in the serum K⫹ concentration can rapidly develop under conditions of increased stress. In this setting, stress-induced increases in catecholamines can result in a shift of K⫹ into the intracellular compartment, predisposing such a patient to complex ventricular arrhythmias. In patients who appear resistant to oral supplements, magnesium levels should be checked. Chronic use of both thiazide and loop diuretics can lead to magnesium deficiency, which, in turn, can result in renal K⫹ wasting. In the setting of magnesium deficiency renal K⫹ wasting will continue unabated until the magnesium deficit is first corrected. An alternative approach is to co-administer an agent that will counteract diuretic-induced renal K⫹ wasting. Inhibitors of the renin-angiotensin-aldosterone system are useful for this purpose. Angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and the direct renin inhibitor (aliskiren) limit the development of hypokalemia when given with diuretics and provide the advantage of further lowering the blood pressure. These agents either block the formation or inhibit the actions of angiotensin II, thus limiting the stimulatory effect of

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angiotensin II on aldosterone release from the zona glomerulosa cells in the adrenal gland. Potassium-sparing diuretics also can be used to counteract the effects of diuretic-induced hyperaldosteronism. Spironolactone is the most direct acting of these in that it blocks aldosterone binding to its cytoplasmic receptor. Triamterene and amiloride indirectly inhibit the kaliuretic effect of aldosterone. These agents decrease the luminal electronegativity in the aldosterone-sensitive distal nephron by blocking Na⫹ reabsorption on the apically located epithelial Na⫹ channel. The decrease in luminal electronegativity creates a less favorable electrochemical gradient for K⫹ secretion. Decreased luminal electronegativity also has the effect of decreasing net acid excretion, thus minimizing the development of metabolic alkalosis characteristically associated with use of loop and thiazide diuretics. K⫹-sparing diuretics also decrease magnesium excretion, allowing for the correction of any magnesium deficit that might underlie loop or thiazide diuretic-induced hypokalemia. All of these agents can be given alone or in fixed-dose combinations with the thiazide diuretics. The most important complication associated with use of these agents is the development of fatal hyperkalemia. As a result, patients should be evaluated carefully for any factors that might predispose to the development of hyperkalemia.17 Furthermore, the serum K⫹ concentration should be followed up closely during the initiation of therapy and whenever the clinical condition changes.

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of amiloride to block this channel accounts for the drugs natriuretic effect. Although less well studied, triamterene is also thought to block Na⫹ reabsorption across this same Na⫹ channel. By inhibiting luminal Na⫹ entry into the cell, amiloride and triamterene limit K⫹ secretion by two potential mechanisms. First, blocking the apical Na⫹ channel prevents the development of a lumen-negative potential that normally provides a favorable driving force for K⫹ secretion. Second, decreased intracellular Na⫹ concentration leads to decreased activity of the basolateral Na⫹-K⫹-ATPase. Decreased activity of the pump will lead to a less favorable diffusion gradient for K⫹ across the apical membrane because the activity of this pump is responsible for maintenance of a high intracellular K⫹ concentration. Thus, all of the K⫹-sparing diuretics qualitatively produce similar effects on the composition of the urine. The effects of spironolactone and the Na⫹ channel blockers are additive because they act by distinct mechanisms. It should be noted that all three of these agents are weakly natriuretic because the bulk of filtered Na⫹ is reabsorbed in more upstream nephron segments. The development of hyperkalemia is a potentially lethal complication of these drugs. This risk is dose dependent and increases in patients with renal failure or those taking K⫹ supplements. Special caution should be used when these drugs are co-administered with other agents that interfere with the renin-angiotensin-aldosterone cascade.18 Such combinations can impair renal K⫹ excretion in an additive fashion.

Hyperkalemia Diuretics associated with the development of hyperkalemia are referred to commonly as K⫹-sparing diuretics. Spironolactone directly antagonizes the activity of aldosterone whereas amiloride and triamterene block the epithelial Na⫹ channel (ENaC) in the distal nephron. All three of these agents increase urinary Na⫹ excretion while at the same time limit the renal excretion of K⫹. Spironolactone blocks the binding of aldosterone to its cytoplasmic receptor in cells primarily located in the cortical collecting duct. As a result, the mechanisms by which aldosterone normally enhances renal K⫹ excretion are inhibited. Spironolactone also has been shown to inhibit aldosterone biosynthesis but only at concentrations far greater than those required to inhibit receptor binding in the kidney. It is not known whether this decrease in biosynthesis importantly limits the increase in aldosterone levels that would otherwise occur in response to spironolactone-mediated increases in the serum K⫹ concentration. Eplerenone is a selective aldosteronereceptor antagonist with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects seen with spironolactone. Amiloride and triamterene act to inhibit Na⫹ transport in principal cells of the initial collecting duct and the cortical collecting duct. In these segments, Na⫹ enters the luminal surface of the cell across the ENaC. The ability

ACID-BASE DISTURBANCES A disturbance in the acid-base balance is one of the metabolic complications associated with use of diuretics. Loop and thiazide diuretics are associated with the development of metabolic alkalosis. Given the widespread use of these particular agents, it is of no surprise that diuretic therapy is the most common cause of metabolic alkalosis encountered in clinical medicine. The carbonic anhydrase inhibitors and the K⫹-sparing diuretics are both associated with the development of metabolic acidosis. However, the mechanism by which acidosis develops differs between these two classes of drugs (Fig. 2). Metabolic Acidosis Acetazolamide

The diuretic that is associated most commonly with the development of metabolic acidosis is acetazolamide. This diuretic acts by inhibiting the enzyme carbonic anhydrase. Given the central role that this enzyme plays in bicarbonate reabsorption in the proximal tubule, administration of this diuretic leads to the development of metabolic acidosis by disrupting the process of bicarbonate reclamation. Acetazolamide inhibits bicarbonate reabsorption through its ability to inhibit luminal carbonic anhy-

Metabolic complications and diuretics

Figure 2. The mechanism by which acetazolamide and K⫹-sparing diuretics (spironolactone, eplerenone, amiloride, triamterene) give rise to metabolic acidosis. EABV, effective arterial blood volume.

drase. This enzyme normally catalyzes the dehydration of carbonic acid (produced when filtered bicarbonate reacts with secreted hydrogen ions) to water and CO2, thereby maintaining a favorable concentration gradient for further H⫹ secretion. The uncatalyzed dehydration of carbonic acid occurs very slowly. By inhibiting the activity of this enzyme, acetazolamide allows for the concentration of luminal carbonic acid to increase. The resultant increase in H⫹ concentration creates an unfavorable concentration gradient for further H⫹ secretion. Because of the lipid solubility of acetazolamide, inhibition of intracellular carbonic anhydrase also contributes to the impairment in proximal bicarbonate reabsorption. Inhibition of the intracellular enzyme will decrease the supply of H⫹ available for the secretory process. In either case, decreased secretion of H⫹ will inhibit reabsorption of filtered bicarbonate. Decreased bicarbonate reabsorption in the early proximal nephron limits the development of a favorable Cl⫺ diffusion gradient that, in turn, normally creates a passive diffusion gradient for Na⫹ reabsorption in the S2 portion of the proximal tubule. As a result, there is increased delivery of bicarbonate as well as NaCl to the distal nephron. Most of the Cl⫺ and part of the Na⫹ is reabsorbed in the loop of Henle. Because the capacity of the distal nephron to reabsorb bicarbonate is limited, significant bicarbonaturia results. Bicarbonate acts as a nonreabsorbable anion, allowing for increased amounts of Na⫹ to be delivered to the distal nephron and, as a result, K⫹ secretion is enhanced. Clinical features associated with the use of acetazolamide are similar to those found in proximal renal tubular acidosis. Patients develop a hyperchloremic metabolic acidosis in association with a bicarbonate diuresis. Increased renal K⫹ excretion leads to hypokalemia. The magnitude of the bicarbonaturia is related directly to the serum bicarbonate concentration. As the serum bicarbonate concentration decreases, the clinical effectiveness of the drug declines in a parallel fashion. This relationship

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explains why the acidosis tends to be mild in severity and not progress despite continued use of the drug. The development of metabolic acidosis makes acetazolamide particularly useful in the treatment of patients with metabolic alkalosis who require diuretic therapy. In edematous states such as congestive heart failure, cirrhosis, and nephrotic syndrome, use of loop diuretics often is complicated by the development of metabolic alkalosis. Normally, the initial approach to correcting alkalosis induced by diuretic therapy is the administration of isotonic saline. However, in these patients saline may be ineffective in correcting the alkalotic state as a result of an inability to correct the hemodynamic factors maintaining the alkalosis. In addition, further volume expansion will increase the severity of edema and possibly precipitate pulmonary edema in those patients with borderline cardiac function. The diuretic and bicarbonaturic effects of acetazolamide make this diuretic particularly attractive in this setting. High-altitude pulmonary edema can be prevented in susceptible individuals by prophylactic administration of acetazolamide.19 Although the mechanism of this protective effect is multifactorial, the development of metabolic acidosis stimulates the respiratory center and has favorable effects on the oxygen disassociation curve. Potassium-Sparing Diuretics

The K⫹-sparing diuretics can be associated with the development of metabolic acidosis. Unlike the carbonic anhydrase inhibitors that affect the process of bicarbonate reclamation in the proximal nephron, these agents interfere with the ability of the distal nephron to regenerate bicarbonate. The mechanism by which these drugs impair distal H⫹ secretion is related to their ability to decrease the luminal electronegativity of the collecting duct and to decrease the availability of buffer (Fig. 2). The K⫹-sparing diuretics decrease the luminal electronegativity of the collecting duct by inhibiting the reabsorption of Na⫹ in this segment. The manner in which this is accomplished, however, differs between the various agents. Amiloride and triamterene directly inhibit Na⫹ reabsorption by blocking the Na⫹ channel located on the luminal membrane (ENaC). Spironolactone inhibits Na⫹ reabsorption indirectly by blocking the binding of aldosterone to its cytoplasmic receptor, thereby inhibiting aldosterone-induced Na⫹ reabsorption. The decrease in luminal electronegativity impairs distal acidification as a result of the decrease in driving force for H⫹ into the tubular lumen. Spironolactone can further limit distal H⫹ secretion because this drug not only inhibits aldosteronestimulated Na⫹ reabsorption but also blocks the direct stimulatory effect of aldosterone on the H⫹ secretory pump. In addition to impairing H⫹ secretion, the decrease in luminal electronegativity also impairs K⫹ excretion. The development of hyperkalemia, in turn, will further limit distal acidification by decreasing ammonia availability to

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act as a urinary buffer. Hyperkalemia limits the availability of ammonia in two ways. First, hyperkalemia decreases ammonia production in the proximal tubule. Second, ammonium transport in the thick ascending limb is inhibited because the large increase in medullary K⫹ concentration effectively competes with ammonium for both paracellular transport as well as transport on the Na⫹-K⫹-2Cl⫺ co-transporter. Net acid excretion decreases as a result of limited buffer availability for titration of secreted H⫹. The nature of the acidosis that develops with K⫹sparing diuretics is a hyperchloremic normal gap acidosis. Hyperkalemia is usually present and in this regard serum chemistries mimic a type 4 renal tubular acidosis. Patients at risk for this complication include those with diseases that are commonly associated with deficiencies in aldosterone. For example, diabetic patients with the syndrome of hyporeninemic hypoaldosteronism are particularly prone to develop a type 4 renal tubular acidosis in which life-threatening hyperkalemia can be present. Similarly, patients with chronic kidney disease are at high risk for this complication. Discontinuation of the drug should suffice in returning serum chemistry values back to baseline. Metabolic Alkalosis Loop Diuretics

The use of loop diuretics is associated commonly with the development of metabolic alkalosis (Fig. 3). Loop diuretics inhibit salt transport in the thick ascending limb of Henle, resulting in a reduction in the extracellular fluid volume. The contraction of extracellular fluid around a fixed concentration of bicarbonate will cause the bicarbonate concentration to increase. This effect has been called a contraction alkalosis. However, the magnitude by which this mechanism contributes to the alkalosis is small as a result of intracellular buffering. Both release of

Figure 3. The generation and maintenance of metabolic alkalosis induced by loop and thiazide diuretics. EABV, effective arterial blood volume; GFR, glomerular filtration rate.

B.F. Palmer

H⫹ by cell buffers and increased uptake of bicarbonate into bone tend to minimize the increase in bicarbonate concentration induced by volume contraction. A much more important mechanism by which loop diuretics induce metabolic alkalosis is related to the ability of these drugs to increase net acid excretion in the distal nephron, thereby increasing the renal input of new bicarbonate. At the same time, these agents lead to alterations in the renal handling of bicarbonate in the proximal nephron such that the increase in serum bicarbonate is sustained. Stated differently, loop diuretics lead to the generation of a metabolic alkalosis by increasing acidification in the distal nephron. At the same time, these drugs maintain the alkalosis by enhancing bicarbonate reclamation in the proximal nephron.20 The generation of metabolic alkalosis through increased net acid excretion in the distal nephron is the result of indirect effects induced by loop diuretics. Diuretic-induced volume contraction leads to secondary hyperaldosteronism. At the same time distal delivery of Na⫹ is increased as a result of the direct effects of the diuretic in the thick limb of Henle. Aldosterone-mediated Na⫹ reabsorption increases the luminal electronegativity of the collecting duct and results in increased H⫹ secretion. Hydrogen ion secretion is also directly stimulated by aldosterone. Diuretic-induced hypokalemia also contributes to increased distal hydrogen ion secretion because the activity of the H⫹-K⫹-ATPase is increased in the setting of hypokalemia. As net acid excretion increases, newly generated bicarbonate is added to the venous blood. In addition to increasing H⫹ secretion in the collecting duct, loop diuretics also have been shown to increase H⫹ secretion in the thick ascending limb of Henle. In this segment, bicarbonate reabsorption is mediated by a Na⫹-H⫹ antiporter located on the apical membrane. Loop diuretics secondarily stimulate the activity of the antiporter by inhibiting NaCl entry across the luminal membrane, decreasing cell Na⫹, and increasing the transmembrane Na⫹ gradient. The quantitative importance of increased HCO3 reabsorption in this segment to the overall increase in distal H⫹ secretion is unknown but may be greater than previously thought. Secondary effects of the loop diuretics also account for the increased capacity of the proximal tubule to reclaim bicarbonate and thereby maintain alkalosis. Diuretic-induced reductions in effective arterial blood volume decrease the glomerular filtration rate and decrease the filtered load of bicarbonate. A decrease in effective circulatory volume also is associated with increased activity of the Na⫹-H⫹ antiporter. Diuretic-induced K⫹ depletion also can affect the kidney’s ability to maintain metabolic alkalosis. K⫹ depletion can lead to further decreases in glomerular filtration rate and filtered load of bicarbonate. In addition, K⫹ depletion has been shown to stimulate rates of proximal and distal tubular H⫹ secretion. Furthermore, hypokalemia stimulates ammonia pro-

Metabolic complications and diuretics

duction, thereby providing for increased buffer capacity for ongoing H⫹ secretion distally. Although these effects of K⫹ depletion on acid-base balance would be predicted to both generate and maintain metabolic alkalosis, K⫹ depletion only mildly increases the plasma bicarbonate concentration in human beings. The blunted increase in serum bicarbonate concentration is accounted for by an inhibitory effect of hypokalemia on aldosterone secretion. This effect will inhibit renal acidification. A final factor that serves to maintain diuretic-induced alkalosis is an increase in the PCO2 concentration. In the setting of metabolic alkalosis, the increase in pH is attenuated by an increase in the PCO2, which results from compensatory hypoventilation. This hypoventilatory response to metabolic alkalosis is limited by the development of hypoxemia such that the PCO2 concentration rarely exceeds 50 to 55 mm Hg. Metabolic alkalosis is not a typical baseline feature of the clinical conditions in which loop diuretics are used most commonly. Nevertheless, these conditions are associated commonly with the development of metabolic alkalosis once diuretic therapy is initiated. In addition, the alkalosis tends to develop rapidly and can be large in magnitude. For example, cirrhosis, congestive heart failure, and nephrotic syndrome are all characterized by a contracted effective blood volume. In the basal state, circulating aldosterone levels already are increased but distal Na⫹ delivery is low. Initiation of diuretic therapy allows for the increased circulating levels of aldosterone to be coupled to increased distal Na⫹ delivery, resulting in stimulated distal acidification. Newly generated bicarbonate is readily reclaimed in the proximal nephron because these patients already have a contracted effective blood volume. The rapid development of metabolic alkalosis in the edematous states should be contrasted to what happens in an otherwise normal individual given loop diuretics. In a euvolemic salt-replete individual the development of metabolic alkalosis tends to be much more gradual in onset and less severe. In this circumstance, baseline aldosterone levels are normal and only begin to increase once the diuretic achieves some degree of volume depletion. It is only at this point that increased distal Na⫹ delivery couples with increased circulating levels of aldosterone and generation of a metabolic alkalosis is initiated. The ability to maintain the alkalosis is related directly to the degree of volume depletion, which is determined by dietary intake of salt, dose of diuretic, and frequency of administration. The ingestion of a high-salt diet serves to minimize any decrease in volume induced by the diuretic, thereby impairing the ability to maintain the alkalosis. By contrast, a diet overly restricted in salt would exacerbate the contraction in extracellular fluid volume and allow for the alkalosis to be maintained. By similar mechanisms, large doses of loop diuretics given at more frequent intervals would tend to increase those

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factors involved in both the generation and maintenance of metabolic alkalosis. Thiazide Diuretics

The thiazide diuretics also can be complicated by the development of metabolic alkalosis. The mechanisms by which the thiazide diuretics lead to alkalosis are identical to those involved with loop diuretics (Fig. 3). The degree of alkalosis tends to be less severe because the physiologic changes induced by these agents are much less in magnitude when compared with the loop diuretics. Treatment

The initial step in treating a patient with diuretic-induced metabolic alkalosis is to discontinue the drug and replenish the K⫹ deficit if present. In those patients in whom the alkalosis is more severe, administration of isotonic saline to expand the extracellular fluid volume can be given. Restoration of the extracellular fluid volume is effective therapy in this situation because volume depletion is a major factor in the maintenance of alkalosis induced by diuretics. In patients with decompensated congestive heart failure in whom saline administration may be hazardous, alternative measures may be necessary. Acetazolamide often is useful in this situation as a way to inhibit proximal bicarbonate reabsorption. Rarely, intravenous administration of ammonium chloride may be indicated in volume overloaded patients with renal disease.

HYPERURICEMIA Uric acid is the final product of purine metabolism in human beings and is excreted mainly by the kidneys. Renal uric acid handling has been the subject of recent reviews.21,22 In brief, uric acid reaches the tubular lumen by glomerular filtration as well as tubular secretion. The majority of filtered and secreted uric acid undergoes reabsorption in the proximal tubule. The human URAT1 (hURAT1) is a high-affinity urate-anion exchanger located on the apical membrane of the proximal tubule and is responsible for the majority of uric acid absorption in this segment of the nephron. The uricosuric effects of probenecid as well as the angiotensin-receptor blocker losartan are secondary to an inhibitory effect on this protein.23 Thiazide diuretics increase the serum uric acid concentration by stimulating uric acid absorption in the proximal tubule (Fig. 4). Thiazides enter the proximal tubular cell from the blood side through a family of organic anion transporters (OAT1 and OAT3) located on the basolateral surface.24 Recent studies have suggested that thiazides then are transported into the lumen in exchange for uric acid by way of the apically located human organic anion transporter 4 (hOAT4).25 The human OAT4 functions as an organic anion-dicarboxylate exchanger but recently has been found to mediate the transport of urate. The accumulation of thiazides within the cell directly stimulates uric acid uptake as the diuretic

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Figure 4. Thiazides are organic anions that are secreted into the lumen of the proximal tubule. These drugs enter the basolateral side of the cell via a family of organic anion transporters (OAT 1 and 3) in exchange for dicarboxylic acids. Thiazides then are secreted into the tubular lumen via hOAT4, driving the reabsorption of urate. Thiazideinduced reductions in effective volume activate the renin-angiotensin system. Angiotensin II stimulates H⫹ secretion into the tubular lumen via activation of the Na⫹/H⫹ antiporter. The resultant increase in cell OH⫺ concentration can further stimulate the reabsorption of urate by way of urate/OH⫺ exchange via hOAT4. hURAT1 is responsible for the majority of uric acid absorption and does so in exchange for several monocarboxylates such as lactate, nicotinate, and pyrazinoate. Luminal losartan and probenecid cause uricosuria secondary to an inhibitory effect on hURAT1 (solid circle, active transport; white circle, passive transport). HCTZ, hydrochlorothiazide.

enters into the lumen of the proximal tubule. Thiazides also indirectly can stimulate uric acid uptake on this transporter through effects resulting from contraction of the extracellular fluid volume. Volume contraction leads to increased H⫹ secretion in the proximal tubule via the apically located NHE3. As a result, cell pH increases, which in turn drives uric acid uptake via hOAT4 as a result of increased urate/OH⫺ exchange.25 Patients treated with thiazide diuretics develop hyperuricemia within a few days after initiation of treatment and this effect does not fade during prolonged administration.26 Discontinuation of thiazide diuretics reduces serum uric acid concentration. The effect of the drug to increase uric acid levels is dose dependent. Treatment of asymptomatic hyperuricemia is not necessary because the increase usually is modest and of little clinical significance. The risk of precipitating a gouty attack primarily occurs in those with a personal or family history of the disease. Should gout develop then the decision to continue therapy needs to be individualized, as is the decision to initiate uricosuric therapy or administer allopurinol.

HYPOCALCIURIA Thiazide diuretics are well known for their Ca⫹⫹-sparing effect. Thiazide-induced hypocalciuria is used as a therapeutic strategy for the treatment of idiopathic hypercalciuria. Decreased urinary calcium excretion leads to a positive calcium balance and accounts for the beneficial effect of these drugs in increasing bone density and reducing the risk of hip fracture.27,28

B.F. Palmer

Thiazides reduce urinary calcium excretion through effects that stimulate calcium reabsorption in both the proximal and distal nephron.29 In the proximal nephron calcium reabsorption is enhanced as a result of extracellular fluid volume contraction. Volume contraction leads to increased proximal salt and water reabsorption. Because there is a tight coupling between the rates of Na⫹ and calcium absorption in this segment, increases in proximal tubule Na⫹ and volume absorption lead to an increase in luminal calcium concentration, which in turn results in more calcium being passively absorbed through the paracellular pathway. Calcium flux through solvent drag also is enhanced under these conditions. In the distal nephron thiazides stimulate Ca⫹⫹ reabsorption by enhancing transcellular flux. Inhibition of the luminal NaCl cotransporter causes cell Na⫹ concentration to decrease, which in turn increases the activity of the basolateral Na⫹/Ca⫹⫹ exchanger.30 The decrease in cell Cl⫺ concentration hyperpolarizes the cell membrane, an effect known to increase the open probability of the apically located epithelial Ca⫹⫹ channel TRPV5.31 The importance of cell membrane hyperpolarization and channel opening versus increased Na⫹/Ca⫹⫹ exchange is still unclear but the net effect of thiazides is increased transcellular flux of calcium from the tubular lumen to blood. Thiazide diuretics occasionally can be complicated by minor increases in the serum calcium concentration. Significant hypercalcemia tends not to occur because even minor increases in the serum calcium concentration will lead to a suppressive effect on parathyroid hormone release. Plasma calcium concentrations greater than 12 mg/dL or persistently increased concentration after drug discontinuation suggests the presence of primary hyperparathyroidism or some other underlying hypercalcemic condition.

HYPOMAGNESEMIA Chronic use of thiazide diuretics leads to renal magnesium wasting. The exact mechanism by which thiazide diuretics induce hypomagnesemia has not been elucidated. In a manner similar to that described with calcium, one would predict that thiazide-induced inhibition of NaCl transport in the distal convoluted tubule should enhance rather than inhibit Mg⫹⫹ absorption. Two observations in experimental models have provided insight into the mechanism of Mg⫹⫹ wasting with thiazides. Histologic studies in rats administered thiazides continuously for 3 days via subcutaneous minipumps showed loss of the structural characteristics of electrolyte transporting epithelia.32 In particular, there was evidence of apoptosis of distal convoluted cells and focal peritubular inflammation. A second study in mice chronically treated with thiazides showed that Mg⫹⫹ wasting was accompanied by down-regulation of the epithelial Mg⫹⫹ channel transient receptor potential channel subfamily M, member 6.33 There were no histologic changes as noted in the

Metabolic complications and diuretics

previous study and the down-regulation was specific for the Mg⫹⫹ channel because the expression of the Ca⫹⫹ channel TRPV5 was unaffected. The main risk of hypomagnesemia is the potential for arrhythmias, however, the clinical significance of magnesium disturbances induced by chronic thiazide diuretic is debated. In the majority of patients who receive these drugs magnesium disturbances are not a major feature and routine monitoring is not indicated. The addition of a K⫹-sparing diuretic will minimize the degree of Mg⫹⫹ wasting associated with thiazide diuretics.

HYPERGLYCEMIA It is well established that hypertension and insulin resistance often co-exist.34-36 Data obtained from large observational studies suggest there is a higher incidence of new-onset type 2 diabetes mellitus in hypertensive patients who are chronically treated with thiazide diuretics (with or without ␤-blocker use), compared with placebo or angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers.37,38 When new-onset type 2 diabetes mellitus is assessed as new cases per 1,000 patients treated for 1 year, the absolute incidence among patients treated by diuretics or ␤-blockers compared with patients who use an alternative drug (or placebo) averages between 5.6 ⫾ 2.3 new cases per 1,000 patients a year.39 Although the association between thiazide use and glucose intolerance is well documented, the severity and significance of the findings are uncertain. Another unresolved issue is whether glucose intolerance is a direct effect of the drug or a consequence of thiazide-induced hypokalemia.40 In a recent review of more than 50 trials in which thiazides were compared with other drugs or placebo a significant inverse relationship was found between the decrease in K⫹ and increase in glucose level.41 For every 1-mEq/L decrease in K⫹ there was approximately a 10-mg/dL increase in glucose. Further strengthening the argument that hypokalemia plays an important role in the genesis of glucose intolerance is the observation that prevention of hypokalemia with K⫹ supplements prevents the development of thiazide-induced glucose intolerance.42 In addition, changes in glucose levels can be normalized after K⫹ repletion in hypokalemic patients. The mechanism of thiazide-induced hyperglycemia is thought to be the result of decreased insulin release from the pancreatic ␤ cell. ATP-sensitive K⫹ channels couple ␤-cell metabolism to electrical activity and thereby play an essential role in the control of insulin secretion.43 The involvement of K⫹ in this process at least raises the possibility that K⫹ depletion might alter ␤-cell insulin release. Impaired insulin release that is reversible with drug discontinuation or K⫹ supplements is in contrast to the persistent insulin resistance typical of patients with type II diabetes. This difference in mechanism of glucose intolerance may help explain the lack of convincing evidence that thiazide-induced diabetes mellitus in-

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creases the incidence of morbid or fatal cardiovascular events.44

DYSLIPIDEMIA Several studies have found that short-term administration of thiazide diuretics adversely affect lipid metabolism. Various types of thiazide diuretics used in high doses increase total cholesterol levels by approximately 4% and increase serum low-density cholesterol levels by 10%. There are lesser effects on very-low-density cholesterol and no changes in high-density cholesterol.45,46 The adverse affect on lipid profiles has been seen mostly with use of higher doses of the drugs. In contrast to short-term studies, long-term trials using thiazide diuretics have not been complicated by changes in the lipid profile, suggesting the dyslipidemic effect of the drugs is short term and resolves over time with chronic use.29 The mechanism by which thiazides may alter lipid metabolism is not known. Thiazide-induced hypokalemia and increased sympathetic nerve activity resulting from volume contraction have been suggested as playing a contributory role.

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B.F. Palmer 31. Nijenhuis T, Hoenderop J, Bindels R. TRPV5 and TRPV6 in Ca (2⫹) (re)absorption: regulating Ca (2⫹) entry at the gate. Pflugers Arch. 2005;451:181-92. 32. Loffing J, Loffing-Cueni D, Hegyi I, et al. Thiazide treatment of rates provokes apoptosis in distal tubule cells. Kidney Int. 1996; 50:1180-90. 33. Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive Ca2⫹ reabsorption and reduced Mg2⫹ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest. 2005;115: 1651-8. 34. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, et al. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350-7. 35. Pollare T, Lithell H, Berne C. Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism. 1990;39:167-74. 36. Reaven GM. Relationship between insulin resistance and hypertension. Diabetes Care. 1991;14 Suppl 4:33-8. 37. Messerli FH, Grossman E, Leonetti G. Antihypertensive therapy and new onset diabetes. J Hypertens. 2004;22:1845-7. 38. Mason JM, Dickinson HO, Nicolson DJ, Campbell F, Ford GA, Williams B. The diabetogenic potential of thiazide-type diuretic and beta-blocker combinations in patients with hypertension. J Hypertens. 2005;23:1777-81. 39. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens. 2006;24:3-10. 40. Chatterjee R, Yeh H, Shafi T, Selvin S, et al. Serum and dietary potassium and risk of incident type 2 diabetes mellitus. Arch Intern Med. 2010;170:1745-51. 41. Zillich A, Garg J, Basu S, Bakris G, Carter B. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension. 2006;48:219-24. 42. Cutler J. Thiazide-associated glucose abnormalities: prognosis, etiology, and prevention: is potassium balance the key. Hypertension. 2006;48:198-200. 43. Koster J, Remedi M, Masia R, et al. Expression of ATP-insensitive KATP channels in pancreatic beta cells underlies a spectrum of diabetic phenotypes. Diabetes. 2006;55:2957-64. 44. Barzilay J, Cutler J, Davis B. Antihypertensive medications and risk of diabetes mellitus. Curr Opin Nephrol Hypertens. 2007;16: 256-60. 45. van Brummelen P, Gevers Leuven JA, van Gent CM. Influence of hydrochlorothiazide on the plasma levels of triglycerides, total cholesterol and HDL-cholesterol in patients with essential hypertension. Curr Med Res Opin. 1979;6:24-9. 46. Weir MR, Moser M. Diuretics and beta-blockers: is there a risk for dyslipidemia? Am Heart J. 2000;139:174-83.