Can naproxen (Nonsteroidal Anti-Inflammatory Drug) cause hyperkalemia (elevated potassium levels)?

Naproxen and Hyperkalemia: Clinical Implications

Yes, naproxen can cause hyperkalemia, particularly in patients with risk factors such as renal impairment, concurrent use of other potassium-affecting medications, or underlying medical conditions that affect potassium homeostasis. The FDA drug label for naproxen specifically lists hyperkalemia as a potential urogenital adverse effect, though it occurs in less than 1% of patients 1.

Mechanism of Action

Naproxen, like other nonsteroidal anti-inflammatory drugs (NSAIDs), can cause hyperkalemia through several mechanisms:

1. Inhibition of prostaglandin synthesis: This reduces renal blood flow and glomerular filtration rate
2. Decreased renin release: Results in hyporeninemic hypoaldosteronism
3. Impaired renal potassium excretion: Particularly in patients with underlying kidney disease

Risk Factors for Naproxen-Induced Hyperkalemia

The risk of developing hyperkalemia with naproxen is significantly higher in patients with:

• Decreased renal function (eGFR <50 mL/min) - associated with a fivefold increased risk 2
• Concurrent use of other potassium-influencing medications:
  • ACE inhibitors or ARBs
  • Potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride)
  • Potassium supplements
  • Calcineurin inhibitors (cyclosporine)
  • Trimethoprim
• Medical conditions:
  • Diabetes mellitus
  • Heart failure
  • Advanced age
  • Adrenal insufficiency

Clinical Presentation and Monitoring

Hyperkalemia may be asymptomatic or present with:

• Muscle weakness or paralysis (rare but reported with naproxen-induced hyperkalemia) 3
• Cardiac conduction abnormalities
• ECG changes (peaked T waves, prolonged PR interval, widened QRS)

Monitoring Recommendations:

• Baseline serum potassium and renal function before starting naproxen in high-risk patients
• Regular monitoring of electrolytes and renal function in patients with risk factors
• More frequent monitoring when naproxen is used concurrently with other medications that can cause hyperkalemia

Management Approach

If hyperkalemia develops while on naproxen:

1. For severe hyperkalemia (>6.0 mmol/L) or with ECG changes:

   • Immediate discontinuation of naproxen
   • Calcium gluconate for cardiac membrane stabilization
   • Insulin with glucose for intracellular potassium shift
   • Consider sodium bicarbonate if acidosis is present

2. For moderate hyperkalemia (5.5-6.0 mmol/L):

   • Consider discontinuation or dose reduction of naproxen
   • Review and adjust other medications that may contribute to hyperkalemia
   • Consider potassium-binding agents if persistent

3. For mild hyperkalemia (>5.0 to <5.5 mmol/L):

   • Monitor closely
   • Review medication regimen
   • Dietary potassium restriction if appropriate

Case Example

A case report described a patient with rheumatoid arthritis and previous mefenamic acid nephropathy who developed hyperkalemia and inappropriate hypoaldosteronism with both indomethacin and naproxen, without major decline in renal function 4. This suggests that preexisting renal disease may predispose patients to type IV renal tubular acidosis with prostaglandin synthetase inhibitors.

Prevention Strategies

1. Careful patient selection: Avoid or use with caution in high-risk patients
2. Medication review: Avoid combinations of multiple potassium-affecting drugs when possible
3. Monitoring: Regular assessment of renal function and serum potassium in high-risk patients
4. Patient education: Advise on dietary potassium restriction if appropriate
5. Consider alternatives: Use alternative analgesics in high-risk patients

Clinical Pearls

• Hyperkalemia with naproxen is more common in patients with decreased renal function, with a significant increase in risk when eGFR is <50 mL/min 2
• The combination of naproxen with ACE inhibitors or ARBs substantially increases the risk of hyperkalemia 5
• Even without significant decline in renal function, naproxen can cause hyperkalemia through hyporeninemic hypoaldosteronism 4
• Paralysis is a rare but potentially serious non-cardiac manifestation of severe hyperkalemia that has been reported with naproxen use 3

In conclusion, while hyperkalemia is an uncommon adverse effect of naproxen (occurring in <1% of patients), clinicians should be vigilant about this potential complication, particularly in patients with risk factors such as renal impairment or concomitant use of other medications that affect potassium homeostasis.