The effect of amiloride on amphotericin B-induced hypokalaemia

David T. Beardena,* and Lance A. Munceyb

a Department of Pharmacy Practice, Albany College of Pharmacy, 106 New Scotland Avenue, Albany, NY 12208; b University of Utah Hospitals and Clinics, Salt Lake City, UT 84132, USA


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Amiloride was administered to 19 oncology patients exhibiting marked amphotericin B-induced electrolyte wasting. Mean serum potassium concentrations increased in the 5 days preceding and following administration (3.4 ± 0.5 versus 3.9 ± 0.8 mmol/L, P = 0.002). A trend towards decreased potassium supplementation was also observed (48.0 ± 66.5 versus 29.4 ± 43.2 mmol/day, P = 0.12). Amiloride is a therapeutic option to decrease potassium wasting in patients being treated with amphotericin B.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Electrolyte disturbances, particularly potassium and magnesium wasting, are a continued problem with amphotericin B use.1 Although use of potassium-sparing diuretics to limit electrolyte wasting has been suggested in patients treated with amphotericin B,2 few published data are available to support their use. A single published trial using amiloride 5 mg bd concomitantly with amphotericin B as prophylaxis against potassium wasting showed a decrease in potassium wasting.3 In the Oncology and Bone Marrow Transplant wards at the University of Utah Hospitals and Clinics, amiloride is occasionally added to amphotericin B therapy for those patients who have demonstrated decreased serum potassium concentrations and a marked increase in potassium supplementation. The purpose of this study was to evaluate the efficacy and safety of amiloride use in this population.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Oncology and bone marrow transplant patients receiving amphotericin B deoxycholate for treatment of suspected or documented fungal infections (doses >=0.3 mg/kg/day) were identified over a 3 year period. The medical records of those patients who had received concomitant amiloride for a minimum of 4 days were evaluated for potassium and magnesium intake, potassium and magnesium supplementation, potassium and magnesium serum concentrations and demographic data. Electrolyte intake was quantified from all parenteral (total parenteral nutrition, maintenance fluids, etc.) and enteral sources. All doses of amphotericin B and amiloride, concomitant medications, and related adverse events were recorded. Differences in electrolyte requirements and serum electrolyte concentrations were compared using a paired t-test for the mean values of the 5 days preceding and following the initiation of amiloride. Significance was defined as P < 0.05.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 19 patients, aged 50.7 ± 20.5 years (mean ± S.D.), were evaluable for study. The underlying diagnoses of the patients were acute myelogenous leukaemia (n = 11), other leukaemias (n = 4) and solid tumours (n = 2). Bone marrow transplants were received by seven patients. More than half of the patients (11/19) received total parenteral nutrition as their primary source of electrolyte intake.

Amphotericin B was dosed at 0.67 ± 0.30 mg/kg for a mean of 21.9 days (range 7–57 days). Amiloride 5 mg bd was started on day 6.2 ± 5.3 of amphotericin B therapy. Amiloride doses were subsequently increased to 10 mg bd in six patients. The duration of amiloride therapy was 14.7 ± 12.6 days.

Serum potassium concentrations before initiation of amphotericin B were 3.8 ± 0.5 mmol/L. After amphotericin B administration, serum potassium concentrations declined to 3.3 ± 0.6 mmol/L, corresponding to the day of amiloride initiation. Daily mean potassium concentrations are shown in Figure 1Go. The mean serum concentrations for the 5 days preceding and following the initiation of amiloride were 3.4 ± 0.5 and 3.9 ± 0.8 mmol/L (P = 0.002), respectively.



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Figure 1. Mean serum potassium concentrations were 3.4 ± 0.5 mmol/L before amiloride initiation ({square}) and 3.9 ± 0.8 mmol/L after amiloride initiation ({blacksquare}) (P = 0.002). The arrow represents the day of amiloride initiation.

 
Total potassium intake was 84.5 ± 44.4 mmol/day before amphotericin B initiation, and peaked at 191.2 ± 126.5 mmol/day the day of amiloride initiation (see Figure 2Go). The mean potassium intake was 153.8 ± 90.0 mmol/day in the 5 days preceding amiloride and 148.8 ± 84.6 mmol/day in the 5 days following amiloride initiation (P > 0.05). Total potassium intake decreased in 9/19 patients, with a mean decrease of 39.4 ± 29.5 mmol/day in this subset.



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Figure 2. Total mean potassium intake ({square}) was 153.8 ± 89.0 mmol/day and 148.8 ± 84.6 mmol/day for days –4 to 0 and 1 to 5, respectively (P = 0.84). Mean supplemental potassium ({blacksquare}) intake for the two study periods was 48.0 ± 66.5 mmol/day versus 29.4 ± 43.2 mmol/day (P = 0.12). The arrow represents the day of amiloride initiation.

 
Potassium supplementation requirements were 48.0 ± 66.5 mmol/day and 29.4 ± 43.2 mmol/day for the 5 day periods before and after amiloride initiation, respectively (P = 0.12). Mean potassium supplementation requirements decreased after the addition of amiloride in 11/19 patients, with a mean decrease of 37.7 ± 32.0 mmol/day for this subset.

No significant differences were seen before and after amiloride addition in magnesium serum concentrations (0.97 ± 0.12 versus 0.99 ± 0.13 mmol/L, P > 0.05), total magnesium intake (14.6 ± 18.2 versus 14.4 ± 8.7 mmol/day, P > 0.05), or supplemental magnesium (0.6 ± 2.5 versus 0.9 ± 3.8 mmol/day, P > 0.05).

Hyperkalaemia was observed in two patients receiving amiloride. Case 1 occurred after an increase in amiloride to 10 mg bd. Increases in potassium content of the total parenteral nutrition had been made for the 2 days before the incident, and potassium intake totalled nearly 200 mmol/ day. The serum potassium increased to 6.9 mmol/L. Amiloride was discontinued and kayexelate administered. The patient was restarted on amiloride 10 days later when the serum potassium level was continually measured near 3.0 mmol/L. Case 2 occurred while the patient was receiving amiloride 10 mg bd. The serum potassium reached 6.2 mmol/L, and amiloride was discontinued. The potassium concentration quickly fell and the patient required 40 mmol/day of intravenous potassium for the 2 days immediately following discontinuation.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Few data have been published on the use of amiloride for patients receiving amphotericin B.4 The only published clinical trial randomized 20 neutropenic patients initiating amphotericin therapy to receive either amiloride 5 mg bd or no additional treatment.3 Dietary intake was fixed, with the majority of the patients receiving standardized hospital diets. Serum potassium was measured, and an algorithm was used to guide potassium supplementation. Urinary potassium excretion and the amount of supplementation required to maintain a plasma potassium >3.5 mmol/L were compared between the groups. Significant differences were observed between the groups with decreases in supplementation (22 ± 28 versus 130 ± 54 mmol/day, P < 0.001) and urinary excretion (49 ± 23 versus 93 ± 29 mmol/day, P < 0.01) in the group receiving amiloride. Plasma potassium was significantly higher in the amiloride group (3.9 ± 0.5 versus 3.3 ± 0.5 mmol/L, P < 0.001). Although a reduction in renal magnesium losses was stated by the authors, these data were not provided. No adverse effects were noted. No further published reports were located through a recent MEDLINE search.4

In the present report, amiloride was added to amphotericin B treatment only when patients began to exhibit excessive potassium requirements. It should be noted that the majority of patients in the current study had acute leukaemias, a population with inherent potassium deficits.5 Initiation was based upon health provider discretion, and was not limited by any pre-set serum electrolyte or supplementation values. This resulted in a large variability in the supplementation given for a specific serum potassium concentration.

Overall, mean total potassium intake was not different for the 5 days before and after amiloride initiation. However, the mean potassium intake (Figure 2Go) shows a trend in reduction following amiloride therapy. A similar trend was observed in potassium supplementation, with the mean supplementation requirements differing by nearly 20 mmol/day in the two study periods. Changes in the serum potassium concentrations were significant with an increase of 0.5 mmol/L after initiation of amiloride, despite no change in total potassium intake. This suggests that the increase may be a result of the activity of amiloride, and not a greater potassium intake. Because of the retrospective nature of the study, urinary potassium excretion was not available.

No changes in serum magnesium concentrations or total intake were observed with amiloride therapy in the present study. The minimal need for magnesium supplementation (mean 0.6–0.9 mmol/day) may have prohibited any differences from being identified. Additionally, the time frame of the current study may have preceded the period of maximal magnesium loss suggested to occur later in amphotericin B therapy.1

Most of the patients observed showed benefits from amiloride therapy, with 16/19 patients exhibiting an increase in serum potassium, a decrease in total potassium intake or a combination of the two. Adverse reactions were limited to excessive increases in potassium. This occurred in two patients who received amiloride 10 mg bd. Hyperkalaemia may be related to the higher doses of amiloride but concurrent increases in potassium intake may have been a confounding factor. Four additional patients received 10 mg bd without incident.

The current report supports the use of amiloride in patients receiving amphotericin B who require increasing amounts of potassium supplementation. Initiation of amiloride in patients with an observed need is a more conservative approach than the prophylactic regimen studied by Smith et al.3 Early utilization of amiloride may be considered in patients with underlying risk factors for hypokalaemia (i.e. leukaemia, cisplatin use, diuretics) in whom a prolonged course of amphotericin is anticipated. The addition of another medication to a patient population receiving multidrug therapy is not recommended in all instances, and should be considered on a case-by-case basis. This retrospective study suggests that amiloride may benefit patients by decreasing total potassium requirements and supplementation, as well as increasing serum potassium concentrations. Careful monitoring of serum electrolytes is still required in all patients. Controlled studies are needed to better characterize the activity of amiloride in this and other patient groups.


    Acknowledgments
 
This study was presented in part at the Thirty-eighth Annual Meeting of the Infectious Diseases Society of America, New Orleans, LA, USA, 7–10 September 2000.


    Notes
 
* Corresponding author. Tel: +1-518-445-7334; Fax: +1-518-445-7302; E-mail: beardend{at}acp.edu Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Barton, C. H., Pahl, M., Vazirir, N. D. & Cesario, T. (1984). Renal magnesium wasting associated with amphotericin B therapy. American Journal of Medicine 77, 471–4.[ISI][Medline]

2 . Denning, D. W. (1998). Invasive aspergillosis. Clinical Infectious Diseases 26, 781–805.[ISI][Medline]

3 . Smith, S. R., Galloway, M. J., Reilly. J. T. & Davies, J. M. (1987). Amiloride prevents amphotericin B related hypokalemia in neutropenic patients. Journal of Clinical Pathology 41, 494–7.[Abstract]

4 . Wazny, L. D. & Brophy, D. F. (2000). Amiloride for the prevention of amphotericin B-induced hypokalaemia and hypomagnesemia. Annals of Pharmacotherapy 34, 94–7.[Abstract]

5 . Milionis, H. J., Bourantas, C. L., Siamopoulos, K. C. & Elisaf, M. S. (1999). Acid–base and electrolyte abnormalities in patients with acute leukemia. American Journal of Hematology 62, 201–7.[ISI][Medline]

Received 30 October 2000; returned 14 February 2001; revised 9 March 2001; accepted 6 April 2001





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