ADVERSE DRUG REACTION SECTION

Possible Metoprolol-Induced Hyperkalemia John Hawboldt, BSP, ACPR, PharmD, and Debra McGrath, BScPharm

Hyperkalemia can be a life-threatening event due to the risk of potentially fatal arrhythmias. Hyperkalemia has been reported in 1.3% (serum potassium greater than 6.0 mEq/mL) to 10% (greater than 5.3 mEq/mL) of patients. Hyperkalemia secondary to beta-adrenergic receptor blockade can occur in 1% to 5% of patients and is more likely to occur in non-cardio-selective beta-blockers versus cardioselective beta-blockers. This case report describes hyperkalemia in a 72-year-old female with diabetes and underlying chronic renal failure receiving metoprolol. Chronically, potassium balance is maintained by the kidney. In acute situations, such as a larger than normal potassium

load, both the kidney and the body’s cells react to maintain normal potassium levels. Generally, hyperkalemia occurs secondary to 3 mechanisms: excessive potassium intake, disturbed cellular uptake of potassium, or impaired renal excretion of potassium. Beta-blockers, when used in patients with comorbidities such as renal dysfunction or insulin insufficiency, can potentially cause hyperkalemia. As demonstrated in this case report, hyperkalemia can occur in patients treated with cardio-selective beta-blockers with concurrent risk factors. Health care professionals need to be aware of this potentially life-threatening event to effectively prevent occurrences of beta-blocker-induced hyperkalemia.

KEY WORDS: Hyperkalemia, beta-blockers, chronic kidney disease, diabetes.

H

YPERKALEMIA HAS BEEN DEFINED as a range of serum potassium concentrations that exceeds 5 to 5.5 mEq/L while not receiving drug therapy.1,2 Depending on the definition, hyperkalemia has been reported to develop in 1.3% (serum potassium greater than 6.0 mEq/L) to 10% (greater than 5.3 mEq/L) of patients.3-9 Complications secondary to hyperkalemia can range from a general feeling of unwellness, heart palpitations, and muscle weakness, to cardiac arrhythmias and/or sudden death. Medications causing hyperkalemia have been cited as the primary or contributory cause in 35% to 75% of hospitalized patients.10 Hyperkalemia secondary to beta-adrenergic receptor blockade is a relatively uncommon event occurring in 1% to 5% of patients.10 This phenomenon is thought to occur more often in patients taking noncardio-selective beta-blockers.11 A search of the Canadian Adverse Drug Reaction Monitoring Program Database reported 7 adverse drug reactions indicating potential beta-blocker-induced hyperkalemia during the period of 1995 to December 2006. The offending agents included atenolol (2 events), metoprolol (4 events), and propranolol (1 event).12 A literature search was conducted up until July 2006 using Medline (“Adrenergic beta-Antagonists” and “Hyperkalemia” MeSH terms), EMBASE, and IPA (both using the key

words “beta-blocker” and “hyperkalemia”) to find all randomized controlled trials, review articles, and case report indicating beta-blocker-induced hyperkalemia. All types of literature (ie, randomized controlled trials, review articles, and case reports) were included, as it was felt that beta-blocker-induced hyperkalemia was a rare event, and thus we wanted to extract all possible literature relating to this phenomenon. We also felt that the volume of literature for review would not be overwhelming. A total of 14 articles were obtained. Eight were review articles on drug-induced and or beta-blocker-induced hyperkalemia10,11,13-18; 6 were case reports describing beta-blocker-induced To whom correspondence should be addressed: John Hawboldt, BSP, ACPR, PharmD, assistant professor, School of Pharmacy, Health Sciences Centre, 300 Prince Philip Dr, St. John’s, NL A1B 3V6, Canada. E-mail: [email protected]. John Hawboldt, BSP, ACPR, PharmD, is an assistant professor at the School of Pharmacy at Memorial University of Newfoundland, St. John’s, NL. Debra McGrath, BScPharm, at the time of this event, was a pharmacy student completing her final structured practical experience rotation. She currently works at a community pharmacy in Victoria, British Columbia, Canada. JOURNAL OF PHARMACY PRACTICE 2006. 19;5:320–325 © 2006 Sage Publications DOI: 10.1177/0897190007300728

METOPROLOL-INDUCED HYPERKALEMIA

Table 1 Case Reports Regarding Use of Beta-Blockers and Hyperkalemia19-24 Reference Arthur, Greenberg 199019 Hamad et al. 200120 McCauley et al. 200221 Nowicki, MiszczakKuban 200222 Ashouri 198523 Antrobus et al. 199324

Beta-Blocker Dosage Form

Patient Comorbidities

Maximum Serum Potassium (mEq/L)

Intravenous labetolol

Renal transplant patients

8.3

Intravenous labetolol

Hemodialysis patients

9.9

Intravenous labetolol

Renal transplant patients

Oral nadolol

Hemodialysis patients

Only indicated as those who developed serum potassium >5.5 7.2 (mean)

Oral metoprolol Oral metoprolol

Diabetic patient with renal dysfunction Patient undergoing cardiopulmonary bypass procedure

hyperkalemia19-24; and 1 was a study conducted to determine adrenergic extrarenal potassium disposal.25 Table 1 describes all case reports of beta-blockerinduced hyperkalemia. This case report will describe the development of hyperkalemia in a diabetic patient with chronic renal failure receiving metoprolol, and it will review potassium physiology. CASE REPORT A 72-year-old woman (162 cm, 85 kg) was admitted to the hospital with an increased incidence of falls, cough, shortness of breath, urinary and stool incontinence, and acute or chronic renal failure secondary to dehydration. The patient had no known drug allergies or had had any known adverse reactions to medications previously. She was diagnosed with community-acquired pneumonia and query congestive heart failure (CHF). The internal medicine resident at time of admission was unable to determine whether the respiratory symptoms were due to lower respiratory tract infection or in fact were due to the possibility of previously undiagnosed/ nondocumented CHF. Echocardiography studies were not completed to diagnose CHF. The patient’s blood pressure on admission was 190/70 mm Hg, with a heart rate of 78 bpm. Her estimated creatinine clearance (CrCl) was determined to be approximately 36 mL/min, serum creatinine (SCr) 1.71 mg/dL, and blood urea nitrogen 31.1 mg/dL, respectively. The patient’s electrolytes were all within normal limits (serum potassium 4.0 mEq/L). The patient’s medical history was significant for hypertension, not adequately controlled with her

9.1 7.2

current medications. She also had a history of a myocardial infarction with a coronary artery bypass graft (2004), hyperlipidemia, hypothyroidism, type 2 diabetes mellitus, gout, anxiety/depression, and chronic renal impairment (usual estimated CrCl approximately 43 mL/min). According to the National Kidney Foundation, Kidney Disease Quality Initiative Outcome guidelines, the patient had stage 3 chronic kidney disease (CKD). Prior to admission, her medications included felodipine 10 mg daily, candesartan 48 mg daily, furosemide 60 mg daily, metoprolol 50 mg twice daily, fosinopril 20 mg daily, enteric coated aspirin 325 mg daily, rosuvastatin 10 mg daily, levothyroxine 0.05 mg daily, insulin NPH & R, citalopram 40 mg at bedtime, bromazepam 6 mg at bedtime, and colchicine 0.6 mg daily. On admission, her candesartan was not ordered, owing to her declining renal function, and the furosemide was reduced to 20 mg daily, as it was believed the acute pulmonary discomfort was not due to CHF. Metoprolol 50 mg twice daily and all of her other medications were ordered according to her preadmission medications. Fosinopril and furosemide were given on day 1 and day 2 of her admission but were then discontinued because of her dehydration. Between admission and day 11 of her hospital stay, her blood pressure, although not as elevated as at admission, was gradually increasing (ranging from 130/60 mm Hg to 160/80 mm Hg and 76 to 80 bpm, respectively). Her serum creatinine was normalizing, and her serum potassium was within normal limits, outlined in Table 2. Day 12 of her hospital stay, the metoprolol dose was increased to 62.5 mg twice daily, because of the gradual increase in the patient’s blood pressure JOURNAL OF PHARMACY PRACTICE 2006(19.5)

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Table 2 Sequence of Events Related to Hyperkalemia and Hospital Admission Metoprolol Dose

Serum Potassium (mEq/L)

Serum Creatinine (mg/dL)

BUN (mg/dL)

Potassium Binder Given

50 mg PO twice daily 62.5 mg PO twice daily 62.5 mg PO twice daily 62.5 mg PO twice daily

4.0 5.4 5.7 5.6

1.7 1.3 1.2 1.3

28 20 24 24

Day 16

50 mg PO twice daily

5.9

1.3

24

Day 17 Day 18 Day 19

Discontinued Discontinued Discontinued

6.0 5.0 4.3

1.5 1.5 1.5

28 33 42

— — — Resonium calcium 15 g PO 3 times daily Resonium calcium 30 g PO 3 times daily Kayexalate 15 g 3 times daily Kayexalate 15 g 3 times daily Kayexalate 15 g once daily, then discontinued

Day of Admission Day Day Day Day

1 12 14 15

Note: BUN = blood urea nitrogen.

(160/80 mm Hg). Later that day, routine laboratory workup revealed hyperkalemia, with a serum potassium level of 5.4 mEq/L. Her renal function was improving at this time (creatinine clearance 46 mL/min). During the period of day 12 to day 14, her serum potassium continued to rise, reaching 5.7 mEq/L, and on day 15, the patient was given resonium calcium 15 g 3 times daily. Resonium calcium (calcium polystyrene sulphonate) is an ion exchange resin. It binds with potassium in the gut forming a complex that prevents absorption and reduces serum potassium concentrations. A marginal drop in potassium was produced (5.6 mEq/L). The dose of metoprolol was then decreased back to a preadmission dose of 50 mg twice daily. Nephrology was consulted and indicated that the increased dose of metoprolol may have caused the increase in potassium in the presence of other comorbidities such as diabetes and chronic renal failure. No other drugs were believed to be contributory except for the possibility of a drug interaction between citalopram and metoprolol. It should be noted that the patient was on both metoprolol and citalopram prior to admission. On day 16, the resonium calcium was increased to 30 g 3 times daily, as the potassium continued to rise to 5.9 mEq/L. The metoprolol was discontinued at this point. On day 17, the serum potassium was 6.0 mEq/L, and 1 dose of the resonium calcium was given but it was then changed to kayexalate 15 g 3 times daily. No reason was documented as to the change to kayexalate. The serum potassium levels dropped to 5.0 mEq/mL the following day. As a result, the dose of kayexalate was decreased a day later from 3 times daily to daily because the serum potassium was within normal limits (4.3 mEq/mL) 322

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and later discontinued. During this time, the SCr remained stable (although increasing slightly) and no other medication changes believed to affect serum potassium were initiated. During the hospital admission, the patient’s blood sugars were controlled and thus did not contribute to the hyperkalemia. The Naranjo probability scale reveals a score of 3, indicating a possible association between metoprolol and the hyperkalemia. DISCUSSION The majority of body potassium is located intracellularly, with only 2% (70 mEq) residing in the extracellular fluid, at a concentration of 3.5 to 5.0 mEq/L.13 The relationship of serum potassium to body potassium is nonlinear; thus, elevations in body potassium can cause rapid and substantial elevations in serum potassium. Chronically, the kidney is responsible for maintaining normal potassium balance. Ninety percent of normal potassium intake is excreted by the kidney (usually via distal tubule and collecting duct secretion), with the remaining 10% excreted via the stool. Acutely, the ability to compensate for large loads of potassium depends on both the kidney’s ability to excrete potassium and the ability of the body to transfer potassium into the cells. In general, hyperkalemia occurs secondary to 3 major mechanisms: excessive potassium intake, disturbed cellular uptake of potassium, or impaired renal excretion of potassium.10 The ability to maintain potassium excretion at near normal levels is usually maintained in patients with renal disease as long as both aldosterone secretion and distal flow are maintained.26 Hyperkalemia generally develops in the patients with renal insufficiency, in a

METOPROLOL-INDUCED HYPERKALEMIA

high-potassium diet, increased tissue breakdown, hypoaldosteronism, or fasting in dialysis patients (which may both lower insulin levels and cause resistance to β-adrenergic stimulation of potassium uptake).27,28 The force that keeps potassium in the cell is a negative voltage.29 This is created by active transport of cations out of the cells by the Na-K-ATPase pump, which exports 3 sodium ions in exchange for 2 potassium ions. Movement of potassium into the cells is facilitated by insulin and the β2-adrenergic receptors through an increase in activity of the Na-K-ATPase pump.30 Insulin deficiency and the hyperosmolality induced by hyperglycemia frequently lead to hyperkalemia in uncontrolled diabetes mellitus, even though the patient may be markedly potassium depleted due primarily to potassium losses in the urine.31 Stimulation of β2 receptors will cause a shift of potassium from the extracellular space into the intracellular space, whereas α1 receptors induce the opposite effect.32 Hyperkalemia can develop secondary to beta-blockers by several mechanisms. First, aldosterone secretion from the adrenal cortex can be suppressed by betablocker-decreased catecholamine-stimulated renin release.33 Second, beta-blockade decreases cellular uptake of potassium.34 Agonist binding to β2 receptors stimulates the formation of cyclic AMP, which acts through protein kinase A to phosphorylate and activate the Na-K-ATPase pump leading to potassium movement into the cells.32,35 Competitive inhibition of these receptors by beta-blockers decreases Na-KATPase function and reduces potassium cell uptake.34-36 Normally, nonselective beta-blocker therapy can cause a rise in serum potassium of up to 0.5 mEq/L.37 Cardio-selective beta-blockers are thought to be less likely to cause substantial increases in serum potassium due to their lack of effect on receptors found in skeletal muscle.37-40 However, in patients with renal failure, diabetes, or both, hyperkalemia secondary to beta-blockers may be more pronounced than in those patients without risk factors.27,28,31 Arthur and Greenburg reported 3 cases of hyperkalemia with intravenous labetolol given for acute hypertension in the post-op recovery room following renal transplantation.19 All 3 patients had undergone normal hemodialysis lasting 3 to 4 hours within 24 hours prior to surgery. All 3 had acceptable serum potassium and were felt to require preoperative hemodialysis. The highest reported serum potassium was 8.3 mEq/L, with the other 2 patients reporting potassiums of 6.0 mEq/L and 7.0mEq/L, respectively.

None of the patients was acidotic, and it was believed that the hyperkalemia was due to acute betaadrenergic suppression from labetolol. Hamad et al described a life-threatening case of hyperkalemia with ventricular tachycardia and hypotension.20 The chronic hemodialysis patient had received intravenous labetolol for a hypertensive emergency that occurred during hemodialysis. Blood tests were significant for serum potassium of 9.9 mEq/L (nonhemolyzed sample). A retrospective review analyzed labetolol and the risk of hyperkalemia in renal transplant patients.21 Of the total 103 charts reviewed, 38 patients received labetolol and 34% of those patients developed hyperkalemia. The authors speculated that labetolol increased the risk of hyperkalemia in patients after transplant. Finally, a prospective study completed on 12 patients evaluated the effect of beta-blockade (nadolol and betaxolol) or placebo on fasting hyperkalemia in hemodialysis patients.22 At study end, both nadolol and betaxolol produced an increase in serum potassium (1.2 ± 0.4 mEq/L and 0.9 ± 0.6 mEq/L, respectively) but only nadolol produced a significant increase (P = .01) when compared to placebo. Ashouri described a case (published in abstract form only) whereby hyperkalemia secondary to metoprolol occurred in a diabetic patient with renal dysfunction.23 The use of metoprolol was associated with 3 episodes of hyperkalemia (9.0, 9.1, and 8.7 mEq/L, respectively). Hyperkalemia was alleviated upon discontinuation of the metoprolol. Of all the cases cited, this was perhaps the most similar to our case of hyperkalemia. Antrobus et al described a case of highdose metoprolol (200 mg BID) causing hyperkalemia in a patient receiving cardiopulmonary bypass.24 In this patient, the serum potassium rose to 7.2 mEq/L intraoperatively. Insulin and glucose were given to treat the hyperkalemia. Again, the authors speculated that the hyperkalemia was due to beta-blockade inhibition of potassium uptake by skeletal muscles. None of the above-mentioned studies indicated as to whether the Naranjo probability scale was conducted to determine an association between the beta-blockers and hyperkalemia. In all of the cases, except that by Ashouri, the patients described were those who were on hemodialysis and were receiving noncardioselective betablockers, or cardioselective beta-blockers at higher than normal doses. This differed from our case, as our patient was not a dialysis patient and received metoprolol, a cardioselective beta-blocker, at a normal to low dose. JOURNAL OF PHARMACY PRACTICE 2006(19.5)

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Our patient received citalopram and metoprolol. Coadministration of these agents may result in increased plasma metoprolol levels. Administration of citalopram 40 mg daily has demonstrated a 2-fold increase in plasma metoprolol.41(p423) Although administration of both drugs produced no significant effects on heart rate or blood pressure, increased levels of metoprolol have been associated with a loss in cardioselectivity. The only other beta-blockers to have a documented drug interaction with citalopram are pindolol and propranolol.42 It is speculated that selective serotonin reuptake inhibitors inhibit CYP2D6 isoenzymes responsible for metabolizing certain betablockers (betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol, propranolol, sotalol, timolol).42 Our patient had been on both metoprolol and citalopram long term; hence, we feel the likelihood of this interaction contributing to the hyperkalemia in a significant manner is unlikely.

10.

CONCLUSION

11.

Our case depicts possible induced hyperkalemia secondary to metoprolol therapy in a patient with underlying diabetes and CKD. Although rare, the potential for hyperkalemia to occur in patients treated with cardioselective beta-blockers with concurrent certain risk factors exists. It can be common for diabetic patients to have renal dysfunction, and also to receive concomitant treatment with beta-blockers for conditions such as hypertension. Moreover, of all betablockers used in the public domain, metoprolol is perhaps one of the more utilized beta-blockers. As this is a possibly underreported occurrence, it is important for health care professionals to be aware of this obscure yet potentially life-threatening event. Thus, health care professionals who have patients with underlying diabetes and CKD receiving metoprolol should closely monitor glycemic control, kidney function, potential drug-drug interactions, and serum potassium to prevent beta-blocker-induced hyperkalemia. If their patients’ blood sugars are temporarily not within target due to reasons such as infectious diseases, and so forth, and/or their kidney disease acutely or chronically worsens, careful monitoring of serum potassium can help prevent a catastrophic event. REFERENCES

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