A Brief Review of the Pharmacology of Hyperkalemia: Causes and Treatment

James M. Wooten, PharmD; Fernanda E. Kupferman, MD; Juan C. Kupferman, MD, MPH

Disclosures

South Med J. 2019;112(4):228-233. 

In This Article

Treating Hyperkalemia

During the past few years, the strategies for treating hyperkalemia have changed somewhat as other drugs for reducing potassium concentrations have become available. Hemodialysis remains the primary treatment for patients with severe hyperkalemia who have developed or who are at risk of developing signs or symptoms of hyperkalemia (eg, electrocardiographic changes consistent with hyperkalemia, hemodynamic changes). Various drugs and techniques can be used to reduce potassium concentrations, and the selection of these treatments is based on the severity of the situation and whether the patient is experiencing any cardiac symptoms. Once therapy is completed, a specific cause for hyperkalemia should be established.[15,16]

The various treatments for hyperkalemia are presented below and illustrated in Supplemental Digital Content Table 3 (http://links.lww.com/SMJ/A142). The second, third, and fourth treatments can be used to reduce potassium concentrations acutely by shifting potassium intracellularly. This reduction is only temporary, however, and more permanent treatments may be necessary.

Intravenous Calcium

Cardiac arrhythmia caused by the depolarizing activity induced by hyperkalemia is the most serious adverse effect of elevated potassium. Intravenous (IV) calcium administration rapidly alters this depolarizing activity induced by the elevated potassium concentration. Calcium antagonizes the action of potassium at the cellular level, raising the threshold resting membrane potential, and thus making the cardiac cells less excitable. It must be noted that the rate of the rising potassium concentration is just as important as the potassium concentration value. Patients with chronic hyperkalemia may have normal ECGs, while patients with sudden spikes in potassium concentrations may have abnormal ECGs.[13,14,17]

Calcium is available for IV administration as either the chloride or gluconate salt, with both available as a 10% solution by weight. There is some controversy as to which calcium salt is the preferred choice. The gluconate salt is the preferred therapy when a central line is not available for administration because it is less likely than calcium chloride to cause tissue necrosis if extravasation occurs. Calcium chloride must be given via a central line. Calcium gluconate requires hepatic metabolism to release the calcium, and this may be impaired if hepatic blood flow is compromised. In addition, calcium chloride contains three times the amount of calcium (compared with calcium gluconate) in each 10 mL dose.[9,13–17]

We note the following:[14–16]

  • IV calcium is always indicated in the setting of hyperkalemia whenever ECG changes are present.

  • Some data suggest that IV calcium always is indicated when the serum potassium is >6.5 mEq/L (millimoles per liter), regardless of whether ECG changes are present, because ECG changes alone may not always be a good indicator of the severity of potassium elevation in a particular patient.

  • Whichever calcium salt is used, IV calcium can be given, in adults, as 10 mL of a 10% calcium gluconate solution (or 10 mL of a calcium chloride solution) for 2 to 3 minutes. The dose of either formulation can be repeated after 5 minutes if the ECG changes persist or recur.

  • A 2005 Cochrane review recommends calcium chloride as the preferred calcium salt in the setting of hyperkalemia because of the threefold increase in calcium when compared to calcium gluconate.[18] Other research groups, however, recommend calcium gluconate because of the greater risk of extravasation with calcium chloride.[16]

  • Use caution with patients who are hyperkalemic and concomitantly taking cardiac glycosides (eg, digoxin) because the administration of IV calcium has led to sudden death.

  • The administration of calcium does not alter the serum concentration of potassium. Calcium merely stabilizes the heart. After calcium is administered, it will be effective for only 30 to 60 minutes; therefore, another treatment that reduces the potassium serum concentration must be used in conjunction with calcium.

Insulin and Glucose

Insulin accelerates the movement of potassium from the extracellular to the intracellular space by the activation of Na+/K+-ATPase. The usual insulin dose administered is 5 to 10 U regular or rapid-acting insulin (eg, insulin lispro, insulin aspart), given IV along with 25 g dextrose (50 mL of a 50% solution), also given IV, to offset hypoglycemia caused by insulin administration. The full hypokalemic effect may take 15 to 30 minutes and may last for 2 to 4 hours. This dose can be repeated every 15 minutes if necessary. Blood glucose monitoring is necessary. Dextrose may be unnecessary if the patient is hyperglycemic (blood glucose >250 mg/dL). More sustained therapy may be necessary.[14,16]

β-agonists

β-Adrenergic agonists also are used to treat hyperkalemia. Stimulation of the β-receptor activates Na+/K+-ATPase, which causes potassium to shift intracellularly. In the Unites States, albuterol is the preferred β-agonist, and it is administered via nebulized inhalation. The usual dose is 10 to 20 mg (mixed with 4 mL normal saline), which is greater than what is normal for a single dose to treat acute bronchospasm. Because of the higher doses, β-1 stimulation may occur, and some patients may experience tachycardia. Not all patients respond the same to albuterol therapy, and potassium concentrations may be reduced only modestly. Effective potassium reduction with β-agonist drugs may not occur in patients taking β-blocking drugs (eg, propranolol, metoprolol, carvedilol). More sustained therapy may be necessary.[14,16] Terbutaline also has been used to lower potassium specifically in patients with chronic kidney disease; however, studies are lacking to recommend this drug over albuterol.[16]

Sodium Bicarbonate

The intravenous administration of sodium bicarbonate, either as a bolus dose of 50 mEq (or 1 mEq/kg of an 8.4% solution) or as a continuous infusion, is believed to work by shifting potassium from the extracellular into the intracellular space. Sodium bicarbonate, however, is recommended only in patients who are both hyperkalemic and acidotic. Various studies have demonstrated that the effectiveness of sodium bicarbonate at reducing an elevated potassium concentration can be somewhat sporadic, inconsistent, and slow acting. Studies also have shown that sodium bicarbonate may be less effective at reducing serum potassium levels in patients who have poor renal function or in patients who are receiving hemodialysis treatments. IV sodium bicarbonate must be used with caution because it can increase fluid load on the patient and can cause hypernatremia and metabolic alkalosis. In addition, IV sodium bicarbonate should not be administered in the same IV line as IV calcium because this may cause precipitation of the calcium in the IV line. More sustained therapy may be necessary.[14,15,18]

Loop Diuretics

The administration of loop diuretics (ie, furosemide) may be the most beneficial in treating hyperkalemia after the initial treatment with drugs that induce an immediate shift of potassium intracellularly. Loop diuretics actually remove excess potassium rather than simply move it from one compartment to another. The usual dose of furosemide for treating hyperkalemia is 40 to 80 mg administered as an IV bolus. Loop diuretics also can be administered by IV infusion. For loop diuretics to be effective, patients must have adequate renal function. Loop diuretics increase sodium and water excretion, necessitating adequate fluid assessment. Fluid loss may increase the risk of dehydration, which can induce renal dysfunction. Patients also must be monitored for overexcretion of other electrolytes (eg, magnesium, sodium, calcium), which may be associated with diuretic administration.[4,19]

Sodium Polystyrene Sulfonate

Sodium polystyrene sulfonate (SPS; Kayexalate) has been in existence since the 1950s. It is classified as a cation-exchange polymer that exchanges sodium for potassium, in addition to other cations such as calcium, ammonium, and magnesium. Once the resin binds the potassium, the resin-potassium complex is excreted in the stool. It has been used for many years as a treatment for both acute and chronic hyperkalemia. Each gram of resin binds up to 1 mEq potassium and liberates 1 to 2 mEq sodium. Because of the potential sodium load, SPS must be used with caution in patients who may not be able to tolerate excess sodium (patients with, for example, congestive heart failure, edema, and hypertension). SPS works best in the colon, where the pH is higher. In adults with hyperkalemia, 15 to 30 g SPS can be given orally. SPS can be constipating, and for many years the SPS product was premixed with sorbitol to counteract this adverse effect. SPS also can be given rectally as a retention enema (30–50 g), although rectal administration may be less effective than the oral product. SPS is not an ideal product because it can have variable effects on potassium and it can take >2 hours to have an effect on the potassium concentration. Repeat potassium concentrations should not be obtained for 2 to 4 hours after an SPS dose to allow enough time for the drug to work.[13–16]

In 2011, the US Food and Drug Administration (FDA) required manufacturers of SPS products to include labeling changes to warn prescribers of the risk of fatal colonic necrosis and other serious gastrointestinal (GI) adverse events, including severe fecal impaction. These adverse effects were more common when SPS was given rectally as an enema with sorbitol. It is now recommended that sorbitol not be given with SPS and other laxatives to be given, if necessary. Care also must be taken when administering SPS with other medications because SPS may prevent the absorption of other drugs.[14]

Patiromer

The FDA approved patiromer (Veltassa) in 2015 for the treatment of hyperkalemia. Patiromer (active ingredient: patiromer sorbitex calcium) is a nonabsorbed potassium-binding polymer with a calcium-sorbitol counterion. Unlike SPS, which exchanges sodium for potassium, patiromer exchanges calcium for potassium. The potassium bound to the polymer is then excreted via fecal elimination. Patiromer is not indicated for life-threatening hyperkalemia. It is considered an option for patients with chronic kidney disease and diabetic patients with a serum potassium >5 mEq/L.[14,20–22]

As with SPS, patiromer works primarily in the colon. The drug can take as long as 7 hours to have an initial effect and may take as long as 48 hours to have its maximal effect. Clinical studies with the drug have shown it to be well tolerated, although it should be avoided in patients with severe constipation, bowel obstruction, or impaction. To date, the patiromer-sorbitol combination has not been shown to cause a problem. Adverse effects include abdominal discomfort, flatulence, and hypomagnesemia. Magnesium concentrations must be monitored closely with patiromer therapy.[14]

Clinical trials with this product have documented efficacy at significantly reducing potassium concentrations in the setting of hyperkalemia. One open-label trial (AMETHYST-DN) demonstrated the effectiveness and safety of patiromer at reducing potassium during a period of 52 weeks.[23] In the OPAL-HK trial, patiromer effectively and safely reduced serum potassium levels in hyperkalemic patients with kidney disease who were receiving renin-angiotensin-aldosterone inhibitors. Other studies have demonstrated similar results.[14,15,23,24]

The starting dose of patiromer in adults is 8.4 g once daily. This dose may be adjusted based on the patient's potassium concentrations. The maximum dose is 25.2 g once daily. Patiromer is available as single-dose packets containing powder that is mixed with water.[14]

Sodium Zirconium Cyclosilicate

Sodium zirconium cyclosilicate (ZS-9, Lokelma) was approved by the FDA for the treatment of hyperkalemia. This drug is an inorganic cation exchanger crystalline that works somewhat differently from SMS and patiromer. ZS-9 binds or "entraps" monovalent cations, specifically potassium and ammonium ions, in the GI tract. It then increases fecal potassium excretion by trapping potassium in the lumen of the GI tract; the binding of potassium reduces the free potassium concentration in the GI lumen, thereby lowering the serum potassium level. ZS-9 is not systemically absorbed; accordingly, the risk of any systemic toxicity is low. The drug appears to work immediately upon ingestion and continuously as it moves through the GI tract. ZS-9 generally takes effect 1 hour after a dose and its maximum effect is seen in 2 to 3 hours. Its use should be avoided in patients with severe constipation, bowel obstruction, or impaction, including abnormal postoperative bowel motility disorders. Edema may be an issue for some patients because the drug contains some sodium, and this must be monitored.[14,15]

Clinical trials have demonstrated efficacy over a sustained period. In the phase 3 HARMONIZE trial, ZS-9 safely and effectively reduced potassium concentrations in outpatients with chronic hyperkalemia. The drug provided a safe and consistent response.[24] Other international trials demonstrated similar effectiveness.[25] In addition, the drug appears equally efficacious in all age groups, races, and sexes. The drug also was deemed to be safe.[15]

Dialysis

Although not considered a pharmacologic treatment option, hemodialysis remains a definitive therapy for hyperkalemia, especially in patients with severe hyperkalemia or patients with moderate hyperkalemia and end-stage renal disease. Hemodialysis can rapidly remove large amounts of potassium and must always be considered in severe cases.

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