Antihypertensive Therapy and Its Effects on Potassium Homeostasis

Abstract

The role of potassium in cardiovascular disease and the importance of preserving potassium balance have emerged as clinical hot points, particularly as they relate to cardioprotective and renoprotective therapies that secondarily promote potassium retention. Antihypertensive medications that most commonly influence serum potassium levels and/or total body potassium include β blockers and potassium‐wasting and potassium‐sparing diuretics as well as angiotensin‐converting enzyme inhibitors and angio‐tensin receptor blockers. Uncertainty exists as to the best way to monitor potassium levels when any of these drug therapies are used, particularly in the setting of chronic kidney disease and/or heart failure. Guidelines for the monitoring of serum potassium levels in the setting of antihypertensive therapy are at best makeshift and often drawn from the know‐how of the treating physician.

The measurement of serum potassium (K⁺), although easily accomplished, is seldom standardized. Indeed, the normal range for K⁺ values is itself highly variable between laboratories; the lower limit fluctuates between 3.5 and 3.8 mmol/L and the upper limit between 5.0 and 5.5 mmol/L. Interpretation of a specific serum K⁺ value initially requires an understanding of sampling conditions. For example, a serum K⁺ value derived from a serum sample (red‐top tube) is typically 0.1 to 0.3 mmol/L higher than one obtained from a plasma sample (green‐ or purple‐top tube). ¹

Blood samples obtained using poor technique can also falsely increase serum K⁺ values (pseudohy‐perkalemia). Prolonged use of a tourniquet above a venipuncture site or extended fist clenching produces tissue hypoxia and promotes the escape of K⁺ from tissues into the plasma compartment. ² Serum K⁺ values also show evidence of a circadian rhythm (average peak‐to‐trough difference ≅0.60 mmol/L, with lowest values at night). ³ In addition, serum K⁺ values transiently decrease after meals as the result of insulin stimulating an intracellular flux of K⁺. These considerations are necessary interpretive elements for serum K⁺ values in those receiving antihypertensive medications known to adversely impact K⁺ homeostasis.

EXTERNAL AND INTERNAL FACTORS INFLUENCING SERUM K⁺

The economy of K⁺ in the body is divided into elements of both internal and external balance with antihypertensive medications able to influence both components.

INTERNAL K⁺ BALANCE AND ANTIHYPERTENSIVE THERAPY

Internal K⁺ balance in large measure relates to factors that encourage the intracellular migration of K⁺ such as insulin and β‐adrenergic stimulation (mainly a β₂‐adrenergic effect). ⁴ Conversely, a lack of insulin and β‐adrenergic blockade can be expected to have the opposite effect on the cellular translocation of K⁺. In this regard, the total body K⁺ content of a 70‐kg adult is approximately 4000 mmol. The large majority of body K⁺ resides intracellularly, with about 60 mmol (<2%) of total body K⁺ located extracellularly. As such, since the quantity of K⁺ located outside cells is so small, slight shifts one way or the other can result in significant changes in serum K⁺ values. ⁵

Reports of small increases in serum K⁺ subsequent to β‐blocker therapy for essential hypertension were widespread by the mid‐1970s. This process was seen with nonselective and cardioselective β blockade as well as with combined α‐β blockade. ⁶ The changes in serum K⁺ concentration that accompany the administration of β blockers arise from internal K⁺ shifts—a mechanism supported by the finding that urinary excretion of K⁺ is not reduced when β blockade increases serum K⁺ values. ⁷

The increment in serum K⁺ from β‐blocker therapy is of minor importance, except in patients with significantly reduced renal function. For example, β‐blocker therapy can increase serum K⁺ values by 1 mmol/L or more in end‐stage renal disease patients. Vigorous physical exercise is normally accompanied by transient hyperkalemia with β blockade, further increasing serum K⁺ concentrations both during and after sustained exercise (Figure). ⁸

Figure.

The effect of β blockade on plasma potassium levels in six healthy volunteers before, during, and after exercise. Pretreatment with propranolol (PR) 80 mg, metoprolol (ME) 100 mg, or placebo (PL) given orally 60 minutes before exercise. The insert illustrates one patient with a more profound response of PR on postexercise hyperkalemia. Adapted with permission from Lancet. 1978;2:424–425. ⁸

Although calcium channel blockers increase the cellular uptake of K⁺, drugs in this class inconsistently effect serum K⁺ concentrations at usual doses. ⁹ , ¹⁰ Intentional ingestion of large amounts of verapamil, however, can significantly reduce serum K⁺ concentrations. In one case, profound hypokalemia (2.8 mmol/L) was seen within 40 minutes of ingesting 4.16 g of immediate‐release verapamil. ¹¹

TREATMENT CONSIDERATIONS

All forms of redistributional hyperkalemia, including those that are medication‐related, evolve independent of the underlying state of total body K⁺ balance. Therefore, laboratory values obtained during such situations cannot be used to accurately gauge whether a true total body excess of K⁺ exists or, in the instance of a mixed picture—a patient with a known basis for K⁺ excess and the presence of factors associated with redistribution—to establish the true level of the excess. In such a setting, usual acute care measures for hyperkalemia should be instituted, since the time course for recovery can be unpredictable. The duration of β blocker‐related redistributional hyperkalemia can be fairly prolonged. This is particularly so when renally cleared β blockers, such as atenolol, are administered to patients with an inherent inability to eliminate K⁺, as in the case of advanced chronic kidney disease.

EXTERNAL K⁺ BALANCE AND ANTIHYPERTENSIVE THERAPY

The gastrointestinal and renal systems are the major determinants of external K⁺ balance, with a normally functioning gut characteristically conserving or eliminating K⁺ based on total body stores. The gastrointestinal abnormalities most relevant to external K⁺ balance include diarrhea and/or vomiting. Of note, magnesium (Mg²⁺) losses can be substantial with sustained diarrhea and may go unrecognized in that serum Mg²⁺ values poorly reflect total body stores of this cation. Total body Mg²⁺ deficiency, with or without significantly reduced Mg²⁺ values, can compromise the body's ability to conserve administered K⁺ and is therefore something to be considered in the case of “refractory hypokalemia.” ¹ Antihypertensive therapy rarely effects changes in serum K⁺ values as a consequence of adverse gastrointestinal effects; however, the occasional patient may experience diarrhea with an antihypertensive medication and in the process develop hypokalemia. This is typically a self‐limiting event that corrects with medication discontinuation.

Renal factors influencing K⁺ balance include urinary flow rate, extracellular fluid volume, sodium (Na⁺) intake, acid‐base balance, mineralocorticoid excess, renal tubular diseases, Mg²⁺ depletion, and level of renal function. ⁵ Alterations in systemic K⁺ balance attributable to antihypertensive medication most typically occur on a renal basis. This is the case for several drug classes, including K⁺‐wasting and K⁺‐sparing diuretics as well as angiotensin‐converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

K⁺‐WASTING DIURETICS

A serum K⁺ value below 3.5 mmol/L, the most common definitional criterion for a diagnosis of hypokalemia, is not an uncommon finding in patients treated with loop or high‐dose thiazidetype diuretics. ¹² During the first several days of thiazide diuretic therapy, plasma K⁺ falls by an average of 0.6 mmol/L (in a dose‐dependent manner) in subjects not taking K⁺ supplements and on an unrestricted Na⁺ diet. In comparison, the average fall (≅0.3 mmol/L) with a loop diuretic is less, particularly with a short‐acting compound such as furosemide. ¹² In diuretic‐treated patients, serum K⁺ values seldom drop below 3.0 mmol/L unless dietary Na⁺ intake is excessive, a state of hyper‐aldosteronism (primary or secondary) is present, and/or a long‐acting diuretic (e.g., chlorthalidone) is being used. Flow‐dependent distal nephron K⁺ secretion, which is enhanced with high Na⁺ intake, with or without an excess aldosterone effect, are the most important factors in the onset of diureticrelated hypokalemia. ¹³ , ¹⁴

The typically mildly lowered serum K⁺ values observed with diuretic therapy serves as a starting point for more significant hypokalemia if epinephrine‐mediated transcellular shifts of K⁺ are interposed, as occurs during acute illness. Therein lies the major risk of diuretic‐related hypokalemia, particularly when conditions that sensitize the myocardium to arrhythmias such as left ventricular hypertrophy, heart failure, and/or myocardial ischemia are present. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸

Two issues warrant comment relative to diureticrelated hypokalemia: first, whether there is a hemodynamic benefit afforded hypokalemic patients if their serum K⁺ value is normalized ¹⁹ and, second, what are the consequences of different doses/combinations of diuretics and/or K⁺‐sparing diuretics on sudden cardiac death. ²⁰ , ²¹ To the first issue, in one series of diuretic‐treated hypokalemic patients (serum K⁺ values <3.5 mmol/L), K⁺ supplementation (60 mmol/d for 6 weeks) increased serum K⁺ by 0.56 mmol/L. This level of change was followed by an average fall of 5.5 mm Hg in mean arterial pressure. ¹⁹

Second, the odds ratios for sudden cardiac death with thiazide monotherapy rise as doses increase from 25 to 100 mg/d. ²⁰ The addition of K⁺ supplements to a thiazide‐type diuretic appear to have little effect on the risk of sudden cardiac death. Alternatively, the risk of sudden cardiac death was substantially reduced in patients receiving a thiazide and K⁺‐sparing diuretic in combination. Differences in serum K⁺ concentrations did not explain the differences between thiazide/K⁺ supplements and thiazides/K⁺‐sparing diuretics. It is tempting to speculate that these between‐group differences derived from the favorable effect of K⁺‐sparing diuretics on Mg²⁺ balance; however, these studies were not designed to test this hypothesis. ²⁰

K⁺‐SPARING DIURETICS

All aldosterone receptor antagonists (ARAs) increase serum K⁺ levels in a dose‐dependent manner. ²² , ²³ There are several variables that govern the incidence of ARA‐related hyperkalemia (the definition of hyperkalemia can be highly variable), with a reduced glomerular filtration rate (GFR) being the single most important variable (Table I). Thus, patients with a primary underlying renal disease (and, in particular, diabetic renal disease) or conditions set apart by a high frequency of accompanying renal failure—as is the case with heart failure—will be most prone to an increase in serum K⁺ values with ARA therapy. ²⁴ , ²⁵ , ²⁶ , ²⁷

Table I.

Risk Factors for Hyperkalemia* With Aldosterone Receptor Antagonist Therapy

Inappropriate dosing**

Spironolactone >25 mg/d

Eplerenone >50 mg/d

Pretherapy serum K+ >4.5 mEq/L

High potassium diet, potassium supplements, or salt substitutes

Diabetes mellitus

Advanced stages of heart failure with accompanying reductions in renal function (typically Clcreat <50 mL/min)†

Volume depletion

Loop and/or thiazide diuretic‐related

Intercurrent illnesses (typically gastrointestinal)

Deterioration in renal function with spironolactone or eplerenone

Related to blood pressure/volume status consideration in the setting of concomitant renin‐angiotensin‐aldosterone system blockade

Older age

Related to level of renal function

Caucasian race

Drugs commonly used to modify potassium homeostasis β Blockers

Nonsteroidal anti‐inflammatory drugs or cyclooxygenase inhibitors

Heparin

Regular and low‐molecular weight

Digoxin intoxication

Trimethoprim

Calcineurin inhibitors

Cyclosporine

Tacrolimus

*Hyperkalemia is typically defined as a serum K+ (potassium) value >6.0 mEq/L; **the dose of spironolactone and eplerenone designated as inappropriate is one in excess of that used in the pivotal heart failure clinical trials. Doses higher than those employed in the clinical trials can be considered as appropriate if the aldosterone receptor antagonist is being given for reasons other than cardioprotection, such as for K+ sparing in a persistently hypokalemic patient or when being used for resistant hypertension; †hyperkalemia with an aldosterone receptor antagonist can still occur at Clcreat (creatine clearance) values >50 mL/min in those with risk factors other than reduced renal function, such as diabetes

Although there are dose‐ranging studies with ARAs in the setting of a normal GFR, there is little such information regarding these compounds when used in reduced GFR states. ²⁷ Heart failure, however, can provide a starting point for understanding the hyperkalemia risk with ARA therapy in chronic kidney disease in that the GFR is often reduced in this disease state. For example, the Randomized Aldactone Evaluation Study (RALES) ²² was preceded by a short, dose‐finding study (dose range, 12.5–75.0 mg/d) in which hyperkalemia (serum K⁺≥5.5 mEq/L) occurred in 13%, 20%, and 24% of patients treated with spironolactone 25, 50, and 75 mg/d, respectively.

It should be noted that spironolactone use has been linked to a reduction in GFR in patients with resistant hypertension—a process that can independently influence the tendency to develop hyperkalemia. In a study by Nishizaka et al., ²⁷ five subjects (three of whom had diabetes) treated with low‐dose spironolactone (12.5–50 mg/d) experienced a fall in GFR in tandem with a substantial reduction in BR With lowering of the spironolactone dose and stabilization of blood pressure, the GFR returned to baseline in three of these subjects. In the remaining subjects, the GFR normalized with discontinuation of the spironolactone. This experience suggests that the acute drop in GFR in these subjects may have related more so to the sub‐acute drop in BP reduction rather than to a direct nephrotoxic effect of spironolactone.

ACE INHIBITORS AND ARBs

Hyperkalemia is an ACE inhibitor‐ and ARB‐associated side effect that has a clear physiologic basis, as is the case for ARAs. ²⁵ , ²⁸ , ²⁹ , ³⁰ , ³¹ ACE inhibitors and ARBs will increase the serum K⁺ value in virtually all treated subjects, but only to a degree (0.1–0.2 mEq/L) that is barely discernible clinically. Hyperkalemia, when it occurs with either of these drug classes, remains highly definitional in nature. To register as an incident case of hyperkalemia relating to ACE inhibitor or ARB therapy, a specific threshold value (generally >5.5–6.0 mmol/L) needs to be reached. This definitional approach results in many patients with a significant numeric change in serum K⁺ values (but not reaching a value of ≥5.5 mEq/L) going unrecognized.

The frequency with which serum K⁺ values should be monitored in an ACE inhibitor‐treated patient should be based on pretherapy K⁺ values, the level of renal function, the presence of diabetes, whether concomitant medications are being given that might influence systemic K⁺ balance, and past occurrences of hyperkalemia (Table I). ²⁵ , ³² Potassium supplements, K⁺‐sparing diuretics, and salt substitutes (≅60 mmol/tsp of potassium chloride) increase the probability of developing hyperkalemia if combined with an ACE inhibitor or an ARB. ²⁵ Nonsteroidal anti‐inflammatory drugs (NSAIDs) and cyclooxygenase inhibitors also can exaggerate the rise in serum K⁺ seen with either an ACE inhibitor or an ARB by reducing aldosterone concentrations and thereby decreasing K⁺ excretion. It is uncommon even under the most extreme circumstances to see more than a 2.0‐mmol/L increase in serum K⁺ values with use of an ACE inhibitor or an ARB. When changes of this magnitude occur, it is generally in conjunction with a sudden fall in GFR, prompted by either the ACE inhibitor or ARB (as is the case with renal artery stenosis or due to a volume‐depleting intercurrent illness).

ACE inhibitor‐/ARB‐related hyperkalemia is class‐and not compound‐specific. There is scant experimental evidence to suggest that one ACE inhibitor or ARB carries a lesser risk of hyperkalemia. If differences in the incidence of hyperkalemia truly exist amongst ACE inhibitors (or ARBs)—as has been described for fosinopril—it is a phenomenon probably coupled to the absence of drug accumulation in chronic kidney disease for certain ACE inhibitors. ³³ , ³⁴ A final consideration is whether ARB therapy is associated with a lesser rate of hyperkalemia than is the case for ACE inhibitors. In this regard, the absolute change in serum K⁺ with an ARB is somewhat less than that observed with an ACE inhibitor. ³¹

TREATMENT CONSIDERATIONS

ACE inhibitors, ARBs, β blockers, and ARAs all have well established outcomes benefits; therefore, even in patients likely to develop hyperkalemia, every effort should be made to implement and/or continue the use of these compounds in high‐risk patients. ACE inhibitor (or ARB) therapy alone (with or without a diuretic) is not a common cause of hyperkalemia. It is only when an ARA, such as spironolactone or eplerenone, is added to an ACE inhibitor or an ARB that the risk of hyperkalemia truly materializes. When an ARA is added to an ACE inhibitor/ARB (with or without a β blocker), dietary K⁺ intake should be preemptively restricted. This maneuver alone may suffice to forestall the onset of hyperkalemia.

Limiting the use of K⁺ supplements in anticipation of a rise in K⁺ values with these therapies is an important consideration. Weekly or biweekly determinations of serum K⁺ values are advisable until a patient is stabilized on a regimen comprised of an ACE inhibitor/ARB and an ARA. Once stabilized, serum K⁺ values can be obtained less frequently, but still need to be obtained regularly. Typically, it takes 2–4 weeks after starting an ARA to arrive at a steady state for K⁺ balance. Serum K⁺ sampling in the setting of ACE inhibitor or ARB therapy alone typically is less intense since the risk of hyperkalemia is less so than when either of these drug classes are combined with an ARA.

The circumstances that most commonly disrupt K⁺ homeostasis after a steady state has been reached for ARA effect (with or without an ACE inhibitor or ARB) are those marked by rapid volume loss, such as diarrheal or upper gastrointestinal illnesses (I, II). Loop and thiazidetype diuretics should also be carefully used in the setting of antihypertensive therapy‐related hyperkalemia; whereas an increase in urine flow rate may facilitate urinary K⁺ excretion, an excessive diuretic response can prove detrimental. Under such circumstances, patients should be advised to discontinue ARA treatment (and ACE inhibitor or ARB therapy) until the intercurrent illness has resolved (or volume contraction is corrected) and their K⁺ status is reevaluated. Once an episode of hyperkalemia has resolved, ACE inhibitor, ARB, and/or ARA therapy can be cautiously reintroduced if the benefit sought from such therapy exceeds the risk of recurrent hyperkalemia.

Table II.

Approach With ARA and/or ACE/ARB Therapy to the Patient Prone to Hyperkalemia

Estimate the GFR to define the specific risk of hyperkalemia.*

Measure serum K+ 1–2 weeks after starting therapy and with a dose increase.

Remind the patient that any intercurrent illness accompanied by volume loss requires physician notification since the risk of hyperkalemia increases under these circumstances.

Provide a low‐potassium diet; determine whether salt substitutes are being used.**

Decrease the dose of any K+ supplement in tandem with beginning therapy.

Prescribe a loop and/or thiazide diuretic in sufficient doses to maintain a consistent urine flow rate.

Excessive diuresis can have an opposing effect on serum K+ values if GFR falls in the process.

ARA therapy can increase the diuretic response to loop and/or thiazide diuretic therapy and can decrease GFR.

Whenever possible, discontinue drugs that interfere with K+ homeostasis:

NSAIDs or COXIBs decrease K+ excretion;

Heparin decreases aldosterone production.

If serum K+ increases >5.0 mEq/L, consider discontinuation or dosage reduction of an ACE inhibitor, ARB, and/or the ARA (often the ARA should be the discontinued drug).

Utilize a reduced dose of an ACE inhibitor or one such as trandolapril or fosinopril that does not accumulate in the setting of renal failure. ARBs also do not accumulate in renal failure states.

Empirically reduce the ARA dose or convert to every‐otherday therapy.†

If spironolactone therapy is the basis for hyperkalemia, then empirically switch to eplerenone.††

ARA=aldosterone receptor antagonist; ACE=angiotensin‐converting enzyme inhibitor; ARB=angiotensin receptor blocker; GFR=glomerular filtration rate; K+=potassium; NSAIDs=nonsteroidal anti‐inflammatory drugs; COXIBs=cyclooxygenase inhibitors; *change in serum creatinine poorly gauges level of renal function. A predictive equation based on serum creatinine, age, gender, race, and body size should be used to estimate GFR. See http:www.nkdep.nih.govhealthprofessionalstoolsindex; **salt substitutes typically have 60 mEq/tsp of potassium chloride; †there is little information available that addresses the survival benefits of spironolactone or eplerenone at doses <25 and 50 mg/d, respectively. Moreover, it is unclear in the patient prone to hyperkalemia whether simple dosage reduction is adequate to correct this tendency; ††this relates to the shorter half‐life and absence of active metabolites for eplerenone; however, head‐to‐head studies that compare equivalent doses of eplerenone and spironolactone for hyperkalemia risk have yet to be undertaken.

CONCLUSIONS

Hyperkalemia, as defined by a serum K⁺ value of >5.5–6.0 mmol/L, can occur with several commonly used antihypertensive therapies. An important management step for antihypertensive medication‐related hyperkalemia is to discontinue the offending medication at the time of the incident. Thereafter, the continued treatment with one or the other of these agents becomes discretionary. Hard and fast rules cannot be put forward for the patient with clinically significant hyperkalemia, and each patient should be managed on an individualized basis.