Diuretic Induced Hypokalemia

DIURETIC INDUCED HYPOKALEMIA

INTRODUCTION

Hypokalemia is a relatively common problem with diuretic therapy. Profound hypokalemia (serum potassium concentrations ≤2.5 to 3.0 meq/L), however, is relatively rare, described in fewer than 10 to 15 percent of patients receiving high doses of diuretics, and generally only in those not receiving potassium supplementation.

The decrease in plasma concentration following prolonged administration of 50 mg of hydrochlorothiazide per day is approximately 0.5 meq/L, whereas the same dose of long-acting chlorthalidone causes a greater fall in serum potassium concentration (0.8 meq/L) [1] . In contrast, short-term administration (three days) of 50 mg of chlorthalidone and 40 mg of furosemide results in a fall in serum potassium concentration of only 0.4 and 0.2 meq/L, respectively.

The incidence and severity of hypokalemia are dose-dependent, occurring much less frequently with lower doses [5,6] . Thus, lower doses of thiazides (eg, 12.5 mg/day of hydrochlorothiazide or chlorthalidone) or loop diuretics are now widely used in the treatment of hypertension because they are as effective in blood pressure reduction with a lesser effect on electrolyte balance.

MECHANISMS

Two factors appear to be responsible for the urinary potassium wasting :

• Increased delivery of sodium and water to the aldosterone-sensitive potassium secretory site in the collecting tubules; and

• Increased secretion of aldosterone due to diuretic-induced volume depletion or due to an underlying disease such as heart failure (show figure 3) [7] .

TIME COURSE

In stable patients on a fixed diuretic dose, potassium loss, like other diuretic-induced fluid and electrolyte complications, occurs only during the first two weeks of therapy before a new steady state is established. Thus, a stable patient with a normal serum potassium concentration at three weeks is not at risk of late hypokalemia unless the diuretic dose is increased, extrarenal potassium losses increase, or dietary potassium intake is reduced.

CLINICAL SIGNIFICANCE

The development of hypokalemia is of greatest concern in patients with underlying heart disease, cirrhosis, or hypertension:

* Potassium depletion can lead to cardiac arrhythmias, particularly in the presence of concurrent digitalis therapy or a serum potassium concentration ≤3.0 meq/L [1] . In addition, hypokalemia may contribute to an increased incidence of sudden death in patients with hypertension and left ventricular hypertrophy.

* Hypokalemia (serum potassium less than 3.5 meq/L) can precipitate hepatic coma in some patients with advanced cirrhosis, due at least in part to increased renal ammonia synthesis. The latter effect is mediated in part by a transcellular potassium-hydrogen exchange.

* Potassium depletion may have two additional deleterious effects in patients with hypertension: it can raise the blood pressure by a mean of 5 to 7 mmHg (probably due in part to concurrent sodium retention); and it can increase the incidence of stroke, independent of other cardiovascular risk factors. On the other hand, potassium supplementation can lower the blood pressure by an average of 6/3 mmHg.

TREATMENT

All patients treated with a diuretic should be monitored for the development of hypokalemia during the first two to three weeks of therapy. In stable patients on a fixed dose of a diuretic (eg, for hypertension), potassium loss occurs only during the first two to three weeks of therapy before a new steady state is established.

Once a steady state is reached, further monitoring is not required, unless the diuretic dose is increased, extrarenal potassium losses increase, or dietary potassium intake is reduced. As an example, increased losses and decreased intake may be seen with gastroenteritis. In such patients, temporary cessation of diuretic therapy for a few days may be appropriate.

The best way to treat diuretic-induced hypokalemia is prevention by using the lowest effective dose. Not surprisingly, the risk of hypokalemia (as well as other diuretic-induced metabolic complications) is dose-dependent. Therapeutic issues vary with the underlying condition being treated.

Hypertension — In most hypertensive patients, 12.5 to 25 mg of hydrochlorothiazide (or its equivalent) produces as great a fall in blood pressure as higher doses, but a much smaller reduction in the serum potassium concentration.

The frequent lack of improved blood pressure control with higher diuretic doses may be related to activation of the renin-angiotensin-aldosterone system: angiotensin II is a potent vasoconstrictor that will tend to counteract the antihypertensive effect of more fluid loss, while hyperaldosteronism will enhance urinary potassium losses.

Low-dose thiazide therapy is not generally used in patients with resistant hypertension, underlying renal insufficiency, or an edematous state. Loop diuretics are preferred in the latter two settings. (See "Optimal dosage and side effects of loop diuretics" and see "Resistant hypertension").

Given the typically small reduction in serum potassium with low-dose thiazide therapy, prophylactic therapy to avoid hypokalemia is not warranted. If hypokalemia does occur, there are two main options: switch to another antihypertensive drug; or treat the hypokalemia with potassium chloride supplements (beginning with 40 meq/day) or with a potassium-sparing diuretic such as amiloride, triamterene, or spironolactone. Among the potassium-sparing diuretics, we prefer amiloride because it has the fewest side effects.

Potassium-sparing agents also spare magnesium [1,9,11] . This is a desirable effect since diuretic-induced magnesium depletion may be directly arrhythmogenic and may also cause hypokalemia that is refractory to potassium repletion alone.

Correction of hypokalemia has the added advantage of producing a small further reduction in blood pressure

Heart failure and cirrhosis — Prophylactic therapy to prevent hypokalemia is an important issue in patients with heart failure and cirrhosis:

* Among patients with heart failure, hypokalemia may precipitate serious arrhythmias. It is recommended that the serum potassium concentration be maintained between 4.0 and 5.0 meq/L. In addition, hyperaldosteronism itself appears to contribute to adverse cardiac events in patients with moderate to severe heart failure due to mineralocorticoid receptors in the heart and vasculature. In such patients, outcomes may be improved with a mineralocorticoid receptor antagonist (spironolactone or eplerenone) (show figure 5). Thus, patients who need chronic therapy for a below goal serum potassium concentration should be treated with a mineralocorticoid receptor antagonist rather than potassium supplements.

The data supporting the cardiac and vascular toxicity of hyperaldosteronism are discussed separately. (See "Use of diuretics in heart failure", section on Improved survival with aldosterone antagonism, and see "Clinical features of primary aldosteronism", section on Cardiovascular risk).

* Among patients with cirrhosis, hypokalemia can promote the development of hepatic encephalopathy, perhaps in part by increasing ammonia production. The serum potassium concentration should be maintained above 3.4 meq/L. Most patients with cirrhosis are already being treated with spironolactone, since it is part of the recommended diuretic regimen. (See "Initial therapy of ascites in patients with cirrhosis", section on Concerns with diuretic therapy and section on Diuretic regimen).

As mentioned above, potassium-sparing agents also spare magnesium [1,9,11] . This is a desirable effect since diuretic-induced magnesium depletion may be directly arrhythmogenic and may also cause hypokalemia that is refractory to potassium repletion alone. (See "Signs and symptoms of magnesium depletion").

PROPHYLAXIS

A separate issue from potassium replacement is the possible role of prophylactic potassium supplementation in patients with heart failure who need aggressive diuresis and have a borderline serum potassium concentration (eg, 4.0 to 4.2 meq/L since the goal is to maintain the serum potassium at a minimum of 4.0 meq/L). There are two approaches in such patients: more frequent monitoring, which we prefer, or prophylactic potassium supplementation.

MONITORING

After initiation of either potassium-sparing diuretics or potassium supplements, potassium levels must be monitored. As with the development of hypokalemia, the rise in the serum potassium concentration with a fixed dose of either potassium chloride or a potassium-sparing diuretic in a stable patient will generally be complete within the first two to three weeks of treatment. Ongoing periodic monitoring is required in patients with heart failure or cirrhosis, who may have progressive disease.

SUMMARY AND RECOMMENDATIONS

Hypokalemia is a relatively common problem with diuretic therapy, with the risk increasing at higher doses. Marked hypokalemia (serum potassium concentrations ≤2.5 to 3.0 meq/L) is uncommon, being described in fewer than 10 to 15 percent of patients receiving high doses of diuretics.

The development of hypokalemia is of greatest concern in patients with underlying heart failure or cirrhosis, as it may lead to arrhythmias and hepatic coma, respectively. In addition, it may lead to a modest elevation in blood pressure in hypertensive patients.

In patients with hypertension who develop diuretic-induced hypokalemia, either another agent can be used, or the hypokalemia can be treated with a potassium-sparing diuretic or potassium supplementation. If a potassium-sparing is chosen, we suggest amiloride, as it has the fewest side effects.

In patients with heart failure or cirrhosis who develop hypokalemia on diuretic therapy, therapy should include a mineralocorticoid receptor antagonist since these drugs are used for reasons other than hypokalemia:

* In patients with heart failure, we recommend a mineralocorticoid receptor antagonist (spironolactone or eplerenone) because of improved survival due in part to blockade of mineralocorticoid receptors in the heart and vasculature (Grade 1B).

Such benefits of mineralocorticoid receptor blockade have not been evaluated in patients with essential hypertension in whom hyperaldosteronism is not a typical feature. However, mineralocorticoid receptor blockers are important in patients with primary aldosteronism.

* We recommend a mineralocorticoid receptor antagonist (spironolactone or, if not tolerated, eplerenone) in patients with cirrhosis and ascites due to increased diuretic efficacy compared to amiloride (Grade 1B).

After initiation of potassium sparing agents or potassium supplements, potassium levels should be monitored, particularly during the first two to three weeks of treatment and after dose adjustments.

Diuretic-induced hypokalemia is best prevented by use of the lowest effective dose.

We suggest not routinely providing prophylactic therapy to prevent hypokalemia (Grade 2C). This is particularly true in patients with hypertension on low-dose thiazide therapy. Patients with heart failure who are undergoing a rapid diuresis require more frequent monitoring of the serum potassium concentration.

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