Electrolytes part 1: potassium and magnesium

Case scenarios

Gavin, 45, is admitted to your hospital for elective surgery on his anterior cruciate ligament (ACL) after rupturing it playing soccer. He is otherwise fit and well, apart from mild hypertension, for which he takes irbesartan with hydrochlorothiazide 150/25 mg daily. Routine blood tests taken at the time of surgery (12 hours ago now) reveal a serum potassium of 3.1 mmol/L (mild hypokalaemia).

Grace, 75, is admitted to hospital with rapid atrial fibrillation (heart rate is 130 bpm), signs of confusion and an infective exacerbation of COPD. She has a history of stage 1 (mild) chronic kidney disease, pulmonary hypertension and subsequent right-sided heart failure secondary to COPD. She takes furosemide 40 mg twice daily, irbesartan 150 mg daily and an indacaterol 110 mcg plus glycopyrronium 50 mcg inhaler, 1 dose daily. A blood test on admission reveals a serum potassium of 3.3 mmol/L (mild hypokalaemia).

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Introduction

Electrolytes play an important role in the function of body tissues including skeletal and cardiac muscle.¹ Electrolytes are elements which carry electrical charge and are maintained in defined concentrations in the body to allow normal function. An imbalance in electrolytes can have detrimental effects on many body tissues; however, often the major concern is cardiac arrhythmia.¹

The factors that influence electrolyte concentrations in the blood are:

• the rate of electrolyte intake
• shifts between intracellular spaces and blood
• electrolyte excretion
• gastrointestinal tract losses.

Electrolyte intake can be dietary or from intravenous (IV) or oral supplementation. Shifts from intracellular spaces to blood can be caused by numerous factors, including cell death (e.g. the release of potassium from cells in tumour lysis syndrome). Electrolyte shifts from blood to intracellular spaces can be caused by certain medicines, such as insulin, which mediates cellular uptake of potassium. The kidneys play a major role in the excretion
of electrolytes such as potassium.¹

Medicines, such as loop diuretics, can cause significant variations in serum electrolyte concentrations and should always be considered as a possible cause of abnormal results. Resources, such as the Australian Medicines Handbook (AMH),² are useful to help determine whether a patient’s medicines may be a cause of their abnormal electrolytes. 

Epidemiology and reference ranges

The prevalence of abnormal potassium and magnesium concentrations is highly variable. Factors that increase the risk of electrolyte disturbances include increasing age, increasing number of comorbidities, dietary changes and acute illness.¹

Electrolyte reference ranges usually describe the range of values between which 95% of the healthy population’s electrolytes levels are expected to lie.^1,3,4 This does not automatically mean that patients with results outside the reference ranges are at risk of complications. It also does not mean that all patients with electrolytes within the reference ranges have an optimal electrolyte concentration. Healthy young patients with electrolytes slightly outside of the reference ranges rarely experience problematic consequences. Older patients with acute cardiac conditions such as rapid atrial fibrillation or acute myocardial infarction may require tighter electrolyte concentrations than standard reference ranges to achieve optimal outcomes. Chronic changes to electrolytes are also less likely to cause acute cardiac complications than acute changes. As laboratories can have different reference ranges due to different techniques used to collect and analyse specimens, the reference range used by the laboratory that provided the result should be considered when reviewing results.^1,3

Potassium

Reference range (serum)
3.5–5.2 mmol/L^3,5

Potassium plays a critical role in the functioning of many bodily processes. Its main role is regulation of nerve and muscle function, including cardiac muscle function.^3,6 Potassium is largely an intracellular electrolyte with concentrations of around 150 mmol/L inside the cell and around 3.5–5.2 mmol/L in the serum (blood).^1,3,5,6 Disturbances in serum potassium affect the activity of Na⁺/K⁺-ATP pumps in muscle tissue, typically causing inappropriate muscle contractions.^7–9 In cardiac myocytes, this can lead to electrocardiogram (ECG) changes and abnormal heart rhythms such as ventricular arrhythmias. In extreme cases, sudden cardiac death can occur.^7–9

Hypokalaemia

Hypokalaemia is a concentration of potassium in the blood below the reference range. The symptoms of hypokalaemia can vary depending on the severity of the condition.⁷ Mild cases of hypokalaemia with serum potassium levels of 3–3.5 mmol/L can be asymptomatic, while severe cases with serum potassium levels of <2.5 mmol/L can lead to life-threatening complications.⁷

Symptoms of hypokalaemia include muscle weakness or cramps, lethargy, constipation, palpitations, nausea or vomiting, tingling or numbness in the limbs.^3,7,8 In severe cases, hypokalaemia can cause cardiac arrhythmias and cardiac arrest.^3,7,8

Hypokalaemia is a relatively common electrolyte disorder.¹⁰ The prevalence of hypokalaemia varies depending on the underlying cause and population studied. In the general population, hypokalaemia is estimated to occur in 1–3% of people.¹¹ However, certain populations may have a higher risk of developing hypokalaemia, such as those with malnutrition or taking diuretics.¹⁰

Common causes of hypokalaemia include^3,8,12:

• Increased aldosterone levels caused by primary hyperaldosteronism or untreated heart failure (aldosterone is the primary hormone regulating renal potassium excretion)
• Medicines, including loop and thiazide diuretics, nebulised or oral beta-agonists and amphotericin B.

The management of hypokalaemia depends on the serum potassium concentration, underlying cause and presence of complications.^1,12 Mild cases of hypokalaemia in young patients without cardiac complications can often be managed with oral potassium supplements.^8,12,13 Intravenous potassium supplementation can be required when the potassium concentration is <3 mmol/L with associated paralysis, hypokalaemia is associated with a cardiac rhythm disturbance, or oral supplementation is not possible.¹² Concomitant oral and IV potassium supplementation should be considered when the patients potassium concentration is <3 mmol/L.¹³

Some references suggest as a rule of thumb, whether potassium is replaced orally or intravenously, each 10 mmol of potassium supplementation increases serum potassium concentration by around 0.1 mmol/L.¹⁴ However, the actual increase in serum potassium from supplements is variable and influenced by a number of factors, including comorbidities, such as kidney disease or heart failure, and the presence of medicines such as diuretics, ACE inhibitors and angiotensin receptor blockers (ARBs).^1,6,15 The Therapeutic Guidelines or local prescribing guidelines, where available, should be consulted for recommended replacement regimens. IV potassium supplementation should be administered at a rate no greater than 20 mmol/hr and ideally at a rate of no greater than 10 mmol/hr when administered via a peripheral cannula.¹³ Faster rates can be administered via central lines terminating in high-flow veins, such as the vena cava, in monitored settings such as an ICU.¹³ Pharmacists play a role in ensuring IV potassium is replaced in appropriate doses and appropriate rates considering the type of line (peripheral or central) the patient has in situ.

The ongoing potassium requirements of the patient also need to be considered when prescribing supplementation. Most people need 1 mmol/kg of potassium per day to replace physiological losses.¹⁶ In patients who are unable to meet daily potassium requirements (e.g. patients who are nil by mouth) or when there are ongoing potassium losses (e.g. patients on large doses of loop diuretic), supplementation doses should account for this.

Aldosterone antagonists, such as spironolactone and eplerenone are not used for the management of acute hypokalaemia.¹² However, given their aldosterone antagonistic effects, these medicines can be useful in the ongoing management of hypokalaemia secondary to hyperaldosteronism.^6,7 They are also often used in patients with activation of the renin angiotensin aldosterone system (RAAS) pathway who have recurrent hypokalaemia from loop diuretics. This includes patients with heart failure and cirrhotic liver disease.

Hypomagnesaemia can cause potassium wasting in the kidneys.^6,17 As such, patients with hypokalaemia resistant to potassium supplementation should have serum magnesium levels assessed and magnesium supplementation initiated where necessary.

An example of a potassium regimen to treat an otherwise healthy 80 kg patient with a serum potassium concentration of 2.8 mmol/L who is nil by mouth before surgery might be^12,13:

• 2 x potassium chloride 14 mmol/tablet (Chlorvescent) immediately orally, then
• 3 x potassium chloride 10 mmol in
  100 mL sodium chloride 0.29% (minibags) given over 1 hour each
• 2 x potassium chloride 40 mmol
  in 1 litre fluid bags given over 10–12 hours each.

This potassium tablets and minibags regimen would be expected to increase the serum potassium levels in this patient by around 0.58 mmol/L, bringing it up to around 3.4 mmol/L. The potassium chloride 1 litre bags (80 mmol total) would be expected to replace natural losses of potassium for the next 24 hours (1 mmol/kg/day). Note, in patients with chronic kidney disease or taking potassium-retaining medicines such as ACE inhibitors or aldosterone antagonists (e.g. spironolactone, eplerenone, finerenone), the amount of potassium supplementation required would be lower.

Many foods are rich in potassium. Although bananas commonly come to mind as a rich source of potassium, baked potatoes, edamame, raisins and salmon all have greater potassium content (g/100 g) than bananas. Individuals with chronic hypokalaemia should have dietitian input to increase dietary potassium.

Hyperkalaemia

Hyperkalaemia is a concentration of potassium in the blood above the reference range.¹¹ The signs and symptoms of hyperkalaemia are variable and depend on the magnitude and chronicity of the hyperkalaemia.¹¹ Common symptoms of hyperkalaemia include muscle weakness, fatigue, muscle cramps and palpitations.⁷ Mild hyperkalaemia can be asymptomatic, while in severe cases hyperkalaemia can lead to cardiac arrhythmia or cardiac arrest.^1,3,11

Common causes of hyperkalaemia include^12,18,19:

• Chronic kidney disease, especially with an eGFR <30 mL/min/1.73 m²
• Medicines, including ACE inhibitors, ARBs and aldosterone antagonists (e.g. spironolactone or eplerenone). Patients with heart failure are often prescribed a combination of these medicines, increasing their risk of hyperkalaemia
• Diabetic ketoacidosis; potassium concentrations are affected by serum pH. Patients with diabetic ketoacidosis have a reduction in serum pH, which causes serum potassium levels to increase due to a compensatory mechanism in the body to exchange intracellular potassium with extracellular hydrogen ions.

The management of hyperkalaemia depends on the patient’s comorbidities and magnitude and chronicity of the serum potassium increase.

Mild hyperkalaemia often requires minimal treatment. Management is focused on careful monitoring, reduction or cessation of causative agents, and a low potassium diet.¹⁸ Management of severe or symptomatic hyperkalaemia can include: reduction or cessation of causative agents; administration of medicines to reduce acute risks of hyperkalaemia (e.g. IV calcium); administration of medicines to reduce total body potassium (e.g. polystyrene sulfonate resin); and administration of medicines to shift potassium into cells (e.g. insulin with glucose).^12,20 Serum potassium concentrations of >6 mmol/L generally require cessation of causative agents with administration of all the acute treatments listed above.¹¹ Patients with acute hyperkalaemia with life-threatening arrythmia or severe ECG changes should have IV calcium gluconate to stabilise the cardiac membrane and prevent arrythmias.¹² Cardiac arrest from complete heart block is likely at serum potassium levels greater than 8 mmol/L.¹¹ However, consideration of the age and comorbidities of the patient are also important when determining which treatments to use.²¹

Insulin shifts glucose into cells, and in the process, potassium is also shifted into cells.^11,18 This shifting of potassium into cells is a temporary effect, and potassium will leak back out of the cells. Recent evidence suggests the traditional dosing of 10 units of soluble short-acting insulin given intravenously,¹² such as insulin aspart or neutral insulin, may be surplus to requirements, and 5 units may be sufficient, although evidence is still limited.^11,18 The magnitude of potassium reduction from 10 units of short-acting insulin is around 1 mmol/L.²²

The glucose administered alongside insulin has no effects on serum potassium and is administered purely to prevent hypoglycaemia. Glucose for this indication is typically administered as 50 mL of 50% glucose over 5 minutes in the same syringe as the insulin.^12,20

Hyperglycaemic patients (with glucose concentrations >11.1 mmol/L) with hyperkalaemia may be treated with insulin alone without glucose.¹⁸

Nebulised salbutamol has similar effects to insulin and is an alternative treatment to reduce serum potassium levels.^18,20 Its mechanism of action is also to temporarily shift potassium into cells. Hypokalaemia can occur in patients administered nebulised salbutamol for other indications such as COPD exacerbations.

In hyperkalaemia, IV calcium is typically administered as calcium gluconate as a 2.2 mmol (10 mL) bolus given over 2–3 minutes with a large flush of saline afterwards.^11,12,20 This does not reduce serum potassium but instead stabilises the cardiac membrane, reducing the risk of pulseless ventricular tachycardia or ventricular fibrillation.

Polystyrene sulfonate resins are appropriate in patients with increased
total body potassium.^11,19 This is common in patients with end-stage chronic kidney disease. They bind to gastrointestinal potassium and prevent its absorption.¹⁹ They may take several hours to have an effect, usually lowering potassium concentration over 1–6 hours.^12,23 The dose depends on the serum potassium level and is often guided by local guidelines.^12,20 Adherence to long-term treatment with polystyrene sulfonate resins is low due to its poor taste and associated nausea and constipation. Patiromer, another potassium binder, has recently become available in Australia; however, it is quite costly and tightly restricted under the Pharmaceutical Benefits Scheme (PBS).²⁴

If dietary modification is required for the management of hyperkalaemia, such as for patients with hyperkalaemia due to kidney disease, dietitian input is recommended to ensure recommendations are individualised to improve adherence.

Magnesium

Reference range (serum)
0.7–1.1 mmol/L^3,5

Magnesium is an essential electrolyte that plays important intracellular roles in the body.^3,12,25,26 More than 300 enzymes require magnesium for their action.²⁵ Magnesium (along with calcium) plays an important role in maintaining bone strength. Over 60% of the body’s stores of magnesium are found in the skeleton.^25,26 The main mechanisms for maintaining or excreting magnesium in the body are through changes in gastrointestinal absorption and/or renal excretion.^25,26 However, magnesium is also excreted in sweat. Magnesium and potassium are often considered together, as hypomagnesaemia is linked to hypokalaemia, and deficits in both electrolytes have similar cardiac effects.^17,25,26

Hypomagnesaemia

Hypomagnesaemia is a concentration of magnesium in the blood below the reference range. Mild cases of hypomagnesaemia may not cause any noticeable symptoms, while severe cases can lead to life-threatening complications, including cardiac arrhythmias.^3,25,26 Some of the most common signs and symptoms of hypomagnesaemia include muscle cramps, tremors, weakness, fatigue, loss of appetite, nausea, vomiting, headaches, confusion and seizures.^3,25–27

Common causes of hypomagnesaemia include^3,12:

• Gastrointestinal disorders, including diarrhoea, intestinal fistulae and malabsorption syndromes
• Medicines, including loop diuretics (e.g. furosemide), thiazide diuretics (e.g. hydrochlorothiazide) and, less commonly, by proton pump
  inhibitors (PPIs)
• Alcohol dependence.

Where possible, treating the cause of the deficiency (e.g. cessation of causative drugs such as PPIs) is the mainstay of management.¹² Mild hypomagnesaemia can be treated with oral magnesium supplements.¹² More severe hypomagnesaemia can require IV magnesium supplementation.¹² Oral magnesium commonly causes diarrhoea and is often poorly tolerated.³ As such, oral magnesium is generally ineffective in acute management of severe hypomagnesaemia. IV magnesium supplementation should be administered slowly to avoid renal excretion of magnesium associated with acutely high serum concentration achieved by rapid infusion.^13,26 A typical regimen can be 10–20 mmol of magnesium infused over 1 hour; however, extending the infusion time may result in better retention of magnesium.^13,12 Increasing dietary intake of magnesium-rich foods, such as leafy green vegetables, nuts and whole grains, can play a role in restoring normal magnesium levels in some patients.²⁶

Hypomagnesaemia is often associated with hypokalaemia.¹⁷ As such, all patients with low serum magnesium should have their serum potassium evaluated. Importantly, serum magnesium levels may not be part of routine blood test screens and may need to be specifically requested.

Hypermagnesaemia

Hypermagnesaemia is a concentration of magnesium in the blood above the references range. This condition is relatively rare and is usually associated with other medical conditions such as kidney failure or cancer (tumour lysis syndrome), lithium use or inappropriate IV magnesium infusions.^12,28,29 It is usually associated with mild symptoms without ECG changes until levels are greater than 3 mmol/L.²⁹ Treatment can include reducing or ceasing magnesium supplementation, IV calcium infusion (to temporarily antagonise toxic effects) and IV sodium chloride (to promote magnesium excretion).^12,29

Knowledge to practice

Recognition and appropriate management of electrolyte disturbances is important. Pharmacists can contribute by assisting in the identification of electrolyte disturbances. When reviewing patients’ medicines, pharmacists should routinely review potassium and magnesium levels if they are available. Pharmacists can also contribute to the management of electrolyte disturbances by providing clinical advice on potential causes (particularly medicine causes), when treatment is required, management strategies (particularly advice on medicine and electrolyte dosing and administration), and by ensuring availability of medicines.

Conclusion

Potassium and magnesium concentration disturbances are relatively common events in medically unwell patients with multiple comorbidities. Management depends on several factors, including the cause, magnitude of the disturbance and comorbidities. Local guidelines are often available to guide management. Pharmacists can play an important role in the identification and management of these disturbances.

Key points

• Electrolytes play an essential role in the function of body tissues. Potassium’s main role is the regulation of nerve and muscle excitability, while magnesium is essential for neuromuscular functions and enzyme systems.
• Mild disturbances to potassium and magnesium concentrations are often asymptomatic, while more severe disturbances can be life threatening.
• Treatment of hyperkalaemia and hypermagnesaemia includes management of the underlying cause, medicines to reduce acute toxic effects, and medicines to remove the electrolytes from the body.
• Treatment of hypokalaemia and hypomagnesaemia includes management of the underlying cause, IV and oral supplements, and other medicines that reduce excretion.

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References

1. Sansom LN ed. Australian pharmaceutical formulary and handbook. 26^th edn. Canberra: Pharmaceutical Society of Australia; 2024.
2. Pharmacy Board of Australia. Guidelines on compounding of medicines. At: www.pharmacyboard.gov.au/Codes-Guidelines.aspx
3. United States Pharmacopoeial Convention. USP-NF compounding compendium. 2023.
4. Therapeutic Goods Administration. Good manufacturing practice – an overview. 2017. At: www.tga.gov.au/good-manufacturing-practice-overview
5. European Medicines Agency. Guideline on Real Time Release Testing (formerly Guideline on Parametric Release). 2012. At: www.tga.gov.au/resources/resource/international-scientific-guidelines/international-scientific-guidelines-guideline-real-time-release-testing-formerly-guideline-parametric-release
6. American Society for Quality. Failure mode and effects analysis (FMEA). At: https://asq.org/quality-resources/fmea
7. Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S). Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments and relevant annexes (PE010).
8. Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S). Guide to Good Manufacturing Practice for Medicinal Products and relevant annexes (PE009).
9. Whyte W, Derks M. Airborne particle deposition in cleanrooms: relationship between deposition rate and airborne concentration. Clean Air and Containment Review. 2016;25:4–10.
10. Victorian Pharmacy Authority. Victorian Pharmacy Authority Guidelines 2023. At: www.pharmacy.vic.gov.au/
11. Pharmacy Regulation Authority SA. Guidelines for the operation of pharmacy premises by pharmacy services providers 2018. At: www.pharmacyauthority.sa.gov.au/
12. Lund W, ed. The pharmaceutical codex. 12thedn. London: Pharmaceutical Press;1994.
13. British Pharmacopoeia Commission. British Pharmacopoeia. London: BPC; 2023.

Our authors

Karl Winckel (he/him) BPharm, Grad Cert Clin Pharm (UK), Dip Pharm Prac (UK), Grad Cert Higher Ed (UQ), Cert Psych Therap (UK), AdvPracPharm is an Advanced Practice credentialed pharmacist and a conjoint pharmacist working between the School of Pharmacy, University of Queensland, and the Princess Alexandra Hospital in Brisbane.

DR Carlos Santini (he/him) MBBS is a clinical pharmacology advanced trainee at the Princess Alexandra Hospital.

Our reviewer

DR Natalie Soulsby (she/her) PhD, MSc Clin Pharm, BSc (Hons) Pharm, AACPA, FPS, FSHP, Adv Pract Pharm