What medications, particularly in patients with a history of gastrointestinal disorders, renal disease, or cardiovascular disease, can cause hypomagnesemia?

Medications That Cause Hypomagnesemia

Proton pump inhibitors (PPIs), loop and thiazide diuretics, and certain antiarrhythmics (particularly dofetilide and sotalol) are the most clinically significant medications that cause magnesium depletion, with PPIs requiring at least 3 months of therapy before hypomagnesemia typically develops. 1, 2

High-Risk Medication Classes

Proton Pump Inhibitors (PPIs)

• PPIs increase the risk of hypomagnesemia, particularly with use exceeding 12 weeks or 3 months of continuous therapy 1, 2
• Hypomagnesemia from PPIs is usually asymptomatic but can manifest as tetany, arrhythmias, and seizures in severe cases 2
• For patients expected to be on prolonged PPI treatment or who take PPIs with medications such as digoxin or diuretics, monitor magnesium levels prior to initiation and periodically during treatment 2
• Most cases of PPI-induced hypomagnesemia occur after at least one year of therapy 2
• Treatment requires magnesium replacement AND discontinuation of the PPI in most patients 2

Diuretics

• Loop diuretics (e.g., furosemide) and thiazide/thiazide-like diuretics (e.g., hydrochlorothiazide, indapamide) cause renal magnesium wasting and should be temporarily stopped during acute illness with volume depletion 1, 3
• Potassium-sparing diuretics (e.g., amiloride, spironolactone) also contribute to magnesium depletion and warrant the same sick-day guidance 1
• Diuretic-induced hypomagnesemia is particularly problematic in heart failure patients and can precipitate serious ventricular arrhythmias 3
• Magnesium deficiency commonly occurs after diuresis with furosemide, ethacrynic acid, and mercurial diuretics 3

Antiarrhythmic Medications

• Dofetilide and sotalol are contraindicated in patients with hypomagnesemia and concurrent diuretic therapy 1
• These QT-prolonging antiarrhythmics require baseline magnesium assessment, as hypomagnesemia increases the risk of torsades de pointes 1
• Avoid other QT interval-prolonging drugs in patients on dofetilide or sotalol, and ensure magnesium levels are normal before initiation 1

Additional Medications Causing Magnesium Loss

• Aminoglycosides, amphotericin B, and cisplatin cause excessive renal magnesium losses 4
• Calcineurin inhibitors and other immunosuppressants can impair renal magnesium handling 5
• Metformin should be temporarily stopped during acute illness with volume depletion (sick-day guidance), though its direct effect on magnesium is less pronounced 1

Clinical Context and Monitoring

Patients Requiring Enhanced Surveillance

• Patients with cardiovascular disease taking digoxin or other medications that may cause hypomagnesemia (particularly diuretics) should have magnesium levels monitored prior to PPI initiation and periodically thereafter 2
• Patients with renal disease have impaired magnesium excretion capacity, making them vulnerable to both hypomagnesemia (from medications) and hypermagnesemia (from supplementation) 4
• Patients with gastrointestinal disorders, particularly those with malabsorption syndromes, short bowel syndrome, or high-output ostomies, are at substantially increased risk 6

Associated Electrolyte Abnormalities

• Hypocalcemia that is refractory to calcium supplementation alone is a hallmark finding in magnesium deficiency, as hypomagnesemia impairs parathyroid hormone release and creates end-organ PTH resistance 6
• Hypokalemia resistant to potassium replacement occurs because magnesium deficiency causes dysfunction of multiple potassium transport systems and increases renal potassium excretion 6
• Both electrolyte abnormalities must be corrected simultaneously, as isolated calcium or potassium replacement will fail without magnesium repletion 6

ECG Manifestations

• Consider magnesium deficiency in patients with prolonged PR, QRS, and QT intervals on ECG, particularly if other electrolyte abnormalities are present 6
• These ECG changes typically occur at magnesium levels of 2.5-5 mmol/L 6

Sick-Day Medication Guidance

Temporary Medication Discontinuation

During acute illness with signs of volume depletion (vomiting, diarrhea, decreased fluid intake), the following medications should be temporarily stopped to prevent further magnesium and electrolyte depletion:

• SGLT2 inhibitors (96% consensus) 1
• Loop diuretics (95% consensus) 1
• Thiazide/thiazide-like diuretics (90% consensus) 1
• Potassium-sparing diuretics (95% consensus) 1
• ACE inhibitors/ARBs (90% consensus) 1
• NSAIDs (95% consensus) 1

Resumption of Medications

• For volume-depleting medications, resume at usual doses within 24-48 hours of eating and drinking normally 1
• Seek assistance from a healthcare provider if symptoms last more than 72 hours 1

Common Pitfalls

• Serum magnesium levels do not accurately reflect total body magnesium status, as less than 1% of total body magnesium is found in the blood 6
• Fatigue and apathy are among the earliest complaints in magnesium deficiency but are nonspecific and often attributed to the underlying disease process 6
• Drug-induced hypomagnesemia is being increasingly recognized but remains underdiagnosed in clinical practice 5, 7, 8
• Multiple medications may act synergistically to deplete magnesium (e.g., PPI + diuretic + digoxin), requiring heightened vigilance in polypharmacy situations 1, 2