What chemotherapy agents, particularly in patients with pre-existing renal or cardiac conditions, can cause hypokalaemia?

Chemotherapy Drugs Causing Hypokalaemia

Platinum-Based Agents

Cisplatin is the most notorious chemotherapy agent for causing hypokalaemia, primarily through renal tubular damage leading to persistent potassium wasting. 1

• Cisplatin causes serum electrolyte disturbances including hypomagnesemia, hypocalcemia, hyponatremia, hypokalaemia, and hypophosphatemia, all related to renal tubular damage 1
• The nephrotoxicity is cumulative and potentiated by aminoglycoside antibiotics, requiring monitoring of serum creatinine, BUN, creatinine clearance, and electrolytes (magnesium, sodium, potassium, calcium) prior to each course 1
• Cisplatin should not be given more frequently than once every 3-4 weeks due to cumulative toxicity 1
• Patients with pre-existing renal or cardiac conditions are at substantially higher risk, as cisplatin is contraindicated in those with pre-existing renal impairment 1
• Profound hypokalaemia from cisplatin can rarely produce hypokalaemic paralysis, requiring aggressive potassium replacement 2
• The mechanism involves direct renal tubular damage with persistent urinary potassium wasting, often accompanied by hypomagnesemia which makes the hypokalaemia refractory to correction 1, 2

Alkylating Agents

Cyclophosphamide and ifosfamide can cause functional Bartter's syndrome with persistent potassium wasting, particularly when used in combination regimens. 3, 4

• High-dose cyclophosphamide (used in regimens like CHOP) has been associated with potassium-wasting nephropathy simulating Bartter's syndrome, characterized by elevated plasma renin and aldosterone levels with urinary potassium wasting 3
• Ifosfamide is associated with electrolyte imbalances including hypokalaemia, particularly at doses of 12.5-16 g/m² where cardiotoxicity rates reach 17% 5
• The risk is amplified in patients with pre-existing cardiac disease or those receiving concurrent cardiotoxic agents 4
• Electrolyte imbalances such as hypokalaemia and hypomagnesemia are recognized risk factors that predispose patients to cardiotoxicity from alkylating agents 4

Anthracyclines

While anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin) are primarily known for cardiotoxicity rather than direct electrolyte disturbances, hypokalaemia significantly increases their cardiac toxicity risk. 5, 4

• Doxorubicin causes dose-dependent cardiotoxicity with 3-5% incidence of heart failure at 400 mg/m², rising to 18-48% at 700 mg/m² 5
• Pre-existing hypokalaemia from other causes (diuretics, other chemotherapy) dramatically increases the risk of anthracycline-induced arrhythmias and sudden death 4
• Patients with hypertension or pre-existing cardiac disease are at higher baseline risk for anthracycline cardiotoxicity, and concurrent hypokalaemia compounds this risk 5
• The combination of anthracyclines with other agents (particularly cyclophosphamide) increases both cardiotoxicity and electrolyte disturbance risk 5

Other Chemotherapy Agents

Several additional chemotherapy agents can cause hypokalaemia through various mechanisms, particularly in high-risk patients. 6, 4

• Methotrexate is nephrotoxic and can cause electrolyte disturbances including hypokalaemia, requiring careful monitoring of renal function and serum electrolytes 6
• Streptozotocin and nitrosoureas are nephrotoxic agents that can lead to electrolyte abnormalities 6
• Fluorouracil may cause cardiotoxicity in >20% of patients, with hypokalaemia as a contributing risk factor 4
• Paclitaxel, etoposide, and vinca alkaloids have been associated with cardiac events, which are exacerbated by electrolyte imbalances 4

Critical Management Considerations for High-Risk Patients

Patients with pre-existing renal or cardiac conditions require aggressive electrolyte monitoring and prophylactic management when receiving these agents. 7, 1

• Target serum potassium should be maintained at 4.0-5.0 mEq/L in all patients receiving cardiotoxic chemotherapy, as both hypokalaemia and hyperkalaemia increase mortality risk 7
• Patients with chronic kidney disease, heart failure, or on RAAS inhibitors face dramatically increased risk of electrolyte disturbances during chemotherapy 7
• Hypomagnesemia must be corrected concurrently, as it is the most common reason for refractory hypokalaemia and makes potassium replacement ineffective 7
• Baseline and regular monitoring should include serum electrolytes (potassium, magnesium, calcium), renal function (creatinine, BUN, creatinine clearance), and ECG in high-risk patients 1, 4
• For patients on diuretics receiving nephrotoxic chemotherapy, consider adding potassium-sparing diuretics (spironolactone 25-100 mg daily) rather than relying solely on oral potassium supplements 7, 8
• Elderly patients are more susceptible to both nephrotoxicity and electrolyte disturbances from chemotherapy 1

Common Pitfalls to Avoid

• Never administer digoxin or other antiarrhythmic agents to patients with uncorrected hypokalaemia from chemotherapy, as this dramatically increases the risk of life-threatening arrhythmias 7
• Failing to check and correct magnesium first is the single most common reason for treatment failure in chemotherapy-induced hypokalaemia 7
• Do not discontinue RAAS inhibitors in patients with cardiac disease who develop hyperkalaemia from renal tubular damage—instead use potassium binders to maintain these life-saving medications 9
• Avoid NSAIDs in patients receiving nephrotoxic chemotherapy, as they worsen renal function and electrolyte abnormalities 7, 8
• Intravascular volume depletion, urinary tract infection, and obstructive uropathy must always be considered when renal function deteriorates during chemotherapy 6