Diuretic use in the elderly: Potential for diuretic-induced hypokalemia

Diuretic Use in the Elderly: Potential for Diuretic-Induced Hypokalemia

WALTER FLAMENBAUM, MD

The more potent ‘kop” diuretics are being used with increasing frequency. The elderly constitute a growing portion of the population undergo@ treatment with diuretics. The atterattons in renal function and pharmacokinetics in the elderly (over 60 years of age) may resuft in the development of certain adverse effects. In patients over 70 years okf, there is a progressive decltne in overall renal function, resulting in a more than 50% decrease in glomerular filtration rate. Most of the pharmacokinetic changes in the ekferty cons&t of atteratkufs resulting In enhanced plasma levels of any given drug; diminished hepatic drug extraction, detoxtfkation/metaboftsm or prodrug conversion; decreased renal excretion of drug; and diminished volume of distribution of drug. Adverse reactions to diuretics may be grouped into

metabolic changes (e.g., hypokalemia), phystotogic alteration (e.g., volume contraction), toxic mantfes- tation (e.g., interstitral nephritis) and allergic or kfto- syncratic phenomena (e.g., rash or thrombocytopenia). There is general agreement that signfficant hypokalemia, particularly among ek!erly patients receiving digitalis gtycoskfes, is significant and re- quires therapy. Diuretic-associated hypokalemia re- flects the potency and duration of a&on of a diuretic, factors modulating potasstum batance in- cludjng dietary intake and concurrent medical processes. The short duration of actlon and greater na- triurests relative to kaliuresfs characteristk of loop diuretics may resutt in a lesser degree of hypokate- mia than that seen with traditsonal thiazkle diuretics.

(Am J Cardiol 1966;57:36A-43A)

T here have been a number of prominent clinical achievements with diuretics in the past 25 years. Of these, the introduction of convenient and safe oral diuretics, in contrast to parenteral mercury-containing compounds, and the availability of potent “loop” or high ceiling diuretics are most notable.1-4 These ac- complishments have resulted in greater safety and ease or convenience of administration, as well as greater breadth of efficacy for diuretics. Unfortunate- ly, both the ease of administering oral diuretic agents and the potency of loop diuretics have resulted in additional problems related to adverse effects.

In addition to these therapeutic advances, there has been an increased understanding of the pharmacokinetics of diuretics in the elderly and greater concern over health problems in the geriatric population5Jj The frequency of diuretic use in the elderly, the unique clinical problems, physical processes and

From the Department of Medicine, Beth Israel Medical Center, New York, New York.

Address for reprints: Walter Flamenbaum, MD, Beth Israel Medical Center, 10 Nathan D. Perlman Place, New York, New York 10003.

30A

pharmacokinetic alterations of the elderly and the basis for diuretic-induced alterations in fluid and electrolyte balance result in diuretic use and hypokalemia being clinically related.7 Certainly there are some factors that are directly due to the development of certain age-related disease processes such as congestive heart failure. There are, however, a number of other salient features of diuretic use in elderly patients that will be highlighted and placed in a useful clinical perspective in this review.

Drug Use in the Elderly Before proceeding to a specific consideration of

diuretics, a brief review of the general characteristics of drug use in the elderly (arbitrarily defined as patients over 60 years of age) will be presented. With aging there are alterations in both pharmacokinetics (drug handling) and pharmacodynamics (drug effect).8-l2 Table I lists some general changes observed in pharmacokinetics. Except for the modest decrement in drug absorption that may occur, the remaining factors promote net effects of increased plasma concentration of drug and prolonged drug half-life (duration of action]. These factors, combined with altered drug

January 24, 1966 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 57 39A

TABLE I Pharmacoklnetics in the Elderly

Drug absorption: usually diminished Hepatic factors:

drug extraction: diminished drug detoxification: diminished prodrug conversion: diminshed

Renal excretion: diminished General factors:

volume of distribution: diminished end-organ effects: diminished

distribution associated with changes in body composi- tion, should lead the clinician to a simple conclusion: Most drugs result in a higher plasma concentration in the elderly on a mg/kg of body weight basis.6 The immediate corollary of this conclusion is that any “dose-related” adverse effect should occur more fre- quently in older patients.

As noted, aging results in diminished drug excretion by the kidney. In reality, the effects of the aging process on renal function are more generalized. First, apart from any superimposed disease processes, there is a general decline in renal function with age. This is manifested as reductions in glomerular filtration rate (GFR) and renal blood flow, decreased breadth of water homeostasis (diminished maximum and minimum urine osmolality] and inability to respond promptly and sufficiently to wide swings in electrolyte (sodium, potassium) intake. 13-18 Second, there are a number of renal diseases and superimposed systemic processes that may be more common in the elderly and affect renal function. The usual decline in renal function solely related to aging (Table IIlg) tends to go unnoticed because the degree of insufficiency is rarely enough to result in azotemia or uremia. However, when concurrent diseases such as bladder outlet obstruction (due to prostatism or uterine prolapse) or progressive renal parenchymal disorders (pyelonephritis, nephrosclero- sis, diabetic nephropathy, etc.) are added to the effects of aging on renal function, the result is a lower GFR than would occur in younger patients with similar or- ganic renal abnormalities. Similarly, extrinsic non- renal diseases, such as congestive heart failure or cirrhosis, which impair renal perfusion, also have a greater net effect on renal function in the older patient.*J6J8

The impact of these changes on the specific use of diuretics may be extrapolated from these general alterations in pharmacokinetics as well as more specific changes in renal function. Physicians usually do not reduce the doses of therapeutic agents based on age alone. Yet the pharmacokinetic alterations of aging make this an important and simple way to avoid dose- related adverse reactions, including diuretic-induced hypokalemia. Second, the reductions in GFR alone that usually occur with aging may change pharmacodynamics enough to require a change in therapy. There is general agreement, for example, that loop diuretics rather than traditional thiazide diuretics are the agents of choice when GFR is reduced by more than 50% .20 Clinicians usually choose a serum creati-

TABLE II Changes in Renal Function Owing to Age

Glomerular Filtration Rate (ml/min)

Age WW

60 65 70 75 60

Men Women

70-80 55-70 67-75 58-66 60-72 48-54 50-58 44-52 46-56 35-49

TABLE III Adverse Reactions to Diuretics

Metabolic: hypokalemia hyperglycemia hyperuricemia hyponatremfa hypercholesterolemia

Physiologic alterations: plasma volume depletion: pre-renal azotemia: (acidosis, hyperkalemla. etc.)

Toxic manifestations: interstitial nephritis enchanced drug nephrotoxicity

Allergic/idiosyncratic: rash thrombocytopenia

nine concentration of 2 mg/dl as a safe dividing line between thiazide efficacy (creatinine concentrations <2 mg/dl] and the need for loop diuretics (creatinine concentrations 22 mg/dl). Older persons, however, may have reductions in GFR out of proportion to their serum creatinine concentration because of loss of muscle mass.

When a patient who has a serum creatinine concentration <2 mg/dl (or even in the “normal” range) does not respond to diuretic therapy, a physician may be- lieve that diuretic resistance has occurred. This conclusion may be based on nonresponsiveness to usual doses of a thiazide diuretic in an elderly patient with edema owing to heart, liver or renal disease. To achieve a diuresis or natriuresis, the physician may use increasing doses of thiazides, resulting in dose-related adverse reactions. In this same situation, loop diuretics may be more efficacious in treating these edematous states with fewer adverse effects. It should be emphasized that low doses of loop diuretics may be effective in the elderly because of alterations in pharmacokinetics.

Hypokalemia Numerous adverse reactions are associated with

diuretic therapy (Table III). Hypokalemia is one very important adverse reaction, of even greater import in elderly patients. Multiple mechanisms contribute to diuretic-induced hypokalemia and depend on potassium homeostasiszl In brief, potassium filtered at the glomerulus is almost completely reabsorbed by the

40A A SYMPOSIUM: CURRENT TRENDS IN DIURETIC THERAPY

TABLE IV Factors Aft ecting Distal Tubule Potassium Secretlon

Sodium-potassium exchange: aldosterone mediated Concentration gradlent (intracellular potassium

concentration): diet acid-base status glucose/Insulin

Electrical gradient: lumen charge Lumen potassium concentration (concentration gradient):

urine flow rate Miscellaneous:

urine, serum or intracellular pH nonaldosterone-mediated sodiumpotasslum exchange

end of the proximal tubule; therefore, ‘alterations in potassium balance reflect changes occurring in distal nephron segments. 22 Indeed, the distal tubule is the primary regulator of potassium secretion and is the nephron site at which significant potassium loss occurs in diuretic-induced hypokalemia.

Under normal circumstances humans are in potassium balance, with dietary intake replacing potassium loss through the renal (major path) or gastrointestinal [minor path) routes. Clinically we may define hypokalemia by its serum level (mild: 3 to 3.5 mEq/liter; mod- erate: 2.5 to 3 mEq/liter; and severe: <2.5 mEq/liter).23 Unfortunately serum potassium concentration is subject to many variables, which makes it an unreliable index of total body potassium content or intracellular potassium levels. Even though clinicians have become dependent on serum potassium concentration as an estimate of potassium deficits or surfeits, we must rec- ognize the inherent limitation of any study of diuretic- induced hypokalemia based solely on serum determi- nations. The question of hypokalemia relative to total body potassium content and the potential adverse effects of even minor changes in serum potassium concentration have been the subject of recent reviews.7,24,25

Multiple factors control distal tubtle potassium secretion and contribute to the hypokalemia associated with diuretic use (Table IV]. The primary pathophysiologic mechanisms resulting in diuretic-induced kaliuresis are: diminished sodium reabsorption at proximal nephron sites as a direct effect of diuretic action on active transport pro&sses, resulting in enhanced delivery of sodium chloride-rich tubule fluid to distal sodium-potassium exchange sites; diuretic-induced volume contraction with renin-angiotensin-aldosterone axis stimulation and enhanced aldosterone-dependent sodium-potassium exchange; and an increase in concentration gradient [lower urine potassium concentration) due to diuresis and diuretic-induced decreases in urine concentrating ability.26 Direct inhibi- tion of potassium reabsorption plays a minor role in the genesis of diuretic-induced hypokalemia.

Hypokalemia and a true total body potassium deficit only develop when there is net loss of potassium due to an inability of potassium intake to keep up with potassium losses. Normally, adult patients take in

more than a sufficient amount of dietary potassium to replace the usual daily losses of this electrolyte. The signs and symptoms of hypokalemia are neither specific nor precisely equated quantitatively to either serum potassium concentration or total body potassium content. Because of the prominent electrophysiologic effects of intracellular and extracellular potassium concentrations, many of the clinical effects of hypokalemia are muscular or neuromuscular in origin.27 Skel- etal muscle changes include weakness, cramps or te- tanny. Neuromuscular alterations such as paresthesias and electrocardiographic abnormalities are also observed. Diffuse and nonspecific symptoms, such as lethargy or constipation, may be related to associated changes in skeletal or smooth muscle, respectively.

Additional effects of potassium deficit include hypokalemic nephropathy and enhanced sensitivity to the toxic manifestations of digitalis glycosides or cardiac arrhythmias. Hypokalemic nephropathy usually occurs in association with severe (serum potassium concentrations <2 mEq/liter) and prolonged potassium deficits.26v28 Diuretic-induced hypokalemia of this magnitude is unusual, except for the surreptitious use of potent diuretics under inappropriate circumstances. The major manifestation of hypokalemic nephropathy is impaired urine concentration and dilution due to changes in loop of Henle function.28 There are other renal changes that result in an inability .to conserve sodium normally and that contribute to the volume contraction observed in these patients, as well as disor- dered acid-base homeostasis, encouraging the mainte- nance of a metabolic alkalosis.

Of greater frequency and clinical import is the role of hypokalemia in the generation of cardiac arrhythmias, either in patients without known cardiac disease or in those patients being treated with digitalis glycosides.7 Hypokalemia alters cardiac cellular electro- physiology and enhances catecholamine-related cardiac irritability-factors that alone or in combination with digitalis result in a propensity for the development of cardiac arrhythmias. A discussion of the spe- cifics of these potassium-induced changes is beyond the scope of this review, as is entering the debate on when and how to treat hypokalemia.7s24s25 Suffice it to say that when patients are receiving digitalis glycoside preparations, most physicians will take measures to treat or avoid diuretic-induced hypokalemia of any magnitude: this may even include decreases in serum potassium concentrations within the normal range. In addition, most physicians will not treat diuretic-induced mild hypokalemia (serum potassium concentration of 3 to 3.5 mEq/liter) in the absence of signs or symptoms, even though direct and indirect evidence suggests the possibility of associated cardiac problems (arrhythmias, sudden death and enhanced morbidity of diuretic-treated mild hypertensiorQ7J9The decision to defer therapy of mild hypokalemia in patients not receiving digitalis must also be viewed in light of the clear-cut problems associated with hyperkalemia that are due to either potassium-sparing diuretics or exoge- nous potassium sources, especially in patients with diminished renal function.


There is also evidence of a greater risk of develop- ing hyperkalemia during the treatment or prophylaxis of hypokalemia in the elderly.2g Given the great potential for mortality associated with hyperkalemia, as op- posed to the potential problems associated with the development of hypokalemia, this is yet another rea- son to try to avoid hypokalemia rather than treat it.

Diuretics and Hypokalemia in the Elderly These features of drug and diuretic use help to fo-

cus on the problem of diuretic-associated hypokalemia in the elderly (Table V). There are a number of issues that are specific to the elderly. Spontaneous dietary intake of potassium plays a major role in potassium homeostasis in patients receiving diuretics, particularly the elderly.30-34 A host of factors contribute to diminished dietary potassium intake in older patients, including financial constraints, decreased mobility and changes in appetite. When these occur in association with continued diuretic-induced kaliuresis, there is a much greater probability of the development of hypokalemia and potassium depletion. Extra dietary potassium sources, such as bananas or orange juice, may be unavailable or too costly in terms of either calories or dollars. It is not surprising, therefore, that lack of potassium intake per se plays a very important role in the genesis of hypokalemia among elderly patients. Other pertinent dietary factors include diminished intake of fluid and salt, which add to the diuretic-induced hypo- volemic state, promoting aldosterone-mediated potassium losses. This may be exacerbated by decreased renal reserve due to age-related loss of renal paren- chyma, which may promote sodium wastage and affect potassium conservation.15J6

Another very important factor is the choice of diuretic, which may influence the development of hypokalemia through several different mechanisms. Long acting diuretics result in prolonged kaliuresis by prolonging distal sodium delivery. They also diminish the time between diuretic dose for compensation of potassium losses (as well as salt and water losses) by dietary intake and normal homeostatic renal mechanisms,25,35J6 This is worsened by altered pharmacokinetics, which invite prescription of larger doses than may be necessary. However, prolongation of kaliuresis may be partially mitigated by changes in pharmacodynamics or end organ (renal) responsiveness. Any disease process affecting renal function may enhance these changes. For example, congestive heart failure prolongs the duration of action of diuretics by decreas- ing renal excretion of drug as well as diminishing hepatic detoxification/metabolism.

The potency of the chosen diuretic may also have effects on potassium balance that are difficult to pre- dict. On the one hand, traditional thiazide diuretics should result in less potassium loss because the magnitude of the kaliuresis is related to the magnitude of the natriuresis. Loop diuretics, however, have a greater ratio of sodium loss to potassium loss, or a higher urinary sodium to potassium ratio.37-41 Stated another way, they may result in less potassium wastage than traditional thiazide diuretics, especially when the

TABLE V Specific Factors Relating to Development of Dlruretlc- Associated Hypokalemla in the Elderly

Decreased dietary potassium intake Diminished renal reserve Use of long-acting thiazide diuretics, in high doses Altered pharmacokinetics/pharmacodynamics due to concurrent

disease (CHF, renal failure, cirrhosis) Concomitant therapy:

catabolic steroids (glucocorticoids) antibiotics (carbenicillin. amphotericin)

CHF = congestive heart failure.

shorter duration of action of loop diuretics is considered. The greater degree of salt and water loss with loop diuretics might itppear to be a negative factor allowing the development of hypovolemia and wors- ening the effects of diuretics on potassium homeostasis. This is offset, however, by their short duration of action, which allows for some repletion of fluid and electrolyte losses between doses. Further, the long term use of any diuretic results in a fixed amount of volume depletion with time. The major difference between traditional thiazide and loop diuretics is the rapidity with which this minimum volume is reached.

These comments may be best viewed by examining the incidence of diuretic-associated hypokalemia. To avoid superimposed pathophysiologic changes due to clinical processes such as congestive heart failure, this is best done by limiting review to patients being treated with diuretics for hypertension.42 There was a high- ly variable incidence of hypokalemia, ranging from 0 to 60%, with traditional thiazides, and 17 to 70% with a longer acting agent such as chlorthalidone. In contrast, the incidence of hypokalemia with furosemide was 4 to 14%, comparable to that observed with other loop diuretics.

Concomitant therapy of other disease processes with certain drugs may aggravate diuretic-induced potassium losses, especially in the elderly. Corticoste- roids result in some degree of potassium wasting either due to their catabolic effects or, in some part, to mild, mineralocorticoid-like changes in distal sodium-potassium exchange .43 Some antibiotics may augment potassium loss by a direct effect on the tubules rather than through nephrotoxicity. In addition, the relation between glucose, insulin and potassium may result in fluctuations in plasma potassium concentration in patients with diabetes mellitus. This effect may be com- pounded by diuretic-induced changes in glucose homeostasis.44 Before concluding that a diuretic caused the hypokalemia or changing diuretics or providing potassium supplement/potassium-sparing diuretics, the clinician should examine the role of concomitant drug therapy to see if a change in nondiuretic medica- tions can achieve the same goal.

Bumetanide and Other Loop Diuretics in Hypokalemia in the Elderly

Diuretics are prescribed for elderly patients for the same reasons as for most adult patients. These include a number of edematous and nonedematous disease

42A A SYMPOSIUM: CURRENT TRENDS IN DIURETIC THERAPY

states that are more prevalent among the elderly, including both congestive heart failure and hypertension. It is easy to depict the hypothetical clinical problems with which the clinician may be presented. The decreased renal function and altered pharmacokinet- its in the elderly result in the potential need for a more potent diuretic and the necessity to use a lower dose of any given agent, respectively. If there are superimposed renal or systemic diseases, they enhance the clinical contributions of changes in renal function or pharmacokinetics. Also, the very nature of the aging process contributes to a net potassium deficit by limiting the extent of compensation or correction of diuretic-induced urinary potassium losses through dietary means alone. Given these circumstances, one can make a case for using some of the shorter acting traditional thiazides or the very short-acting loop diuretics, depending on the goals of therapy.

Current studies suggest that bumetanide has features that parallel those of furosemide as a loop diuretic.45 Both furosemide and bumetanide have a prompt onset of action, within 40 to 60 minutes, given either orally or intravenously. a0941 In addition, most of their diuretic and natriuretic effects are completed within a relatively short period of time, usually within 4 to 6 hours.40,41 Either bumetanide or furosemide may be used in patients with renal insufficiency, although these patients may require some increase in dose to achieve a diuresis.18,40v41r46*47 Although in most settings these 2 drugs are considered to be interchangeable, some bumetanide features make it of particular benefit in the elderly. Bumetanide appears to have both a more rapid onset and a shorter duration of activity than furosemide, allowing for less marked changes in fluid and electrolyte homeostasis.40,41,4*-51 In addition, it may have less kaliuresis for a given natriuresis, po- tentially resulting in lesser frequency or degree of hypokalemia.52-54 There is also evidence from animal and clinical studies that bumetanide has a lesser potential for ototoxic effects.55

Conclusions In summary, the incidence of clinically significant,

severe diuretic-induced potassium depletion is relatively small. However, the incidence and clinical im- plications of potassium depletion may be greater in the elderly receiving diuretics. When diuretics are part of a therapeutic regimen in older patients, the risks of potassium loss can be minimized by considerations of altered drug metabolism, alteration in dosage, interval or potency of diuretic selected and judicious use of potassium supplementation.58

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Diuretic use in the elderly: Potential for diuretic-induced hypokalemia