Do Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) cause Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), particularly in an older adult patient with a history of moderate hyponatremia and mild hyperkalemia?

ACE Inhibitors and ARBs: SIADH Risk and Electrolyte Disturbances

ACE inhibitors and ARBs rarely cause SIADH, but when they do, the primary electrolyte imbalance is hyponatremia; however, the far more common and clinically significant electrolyte disturbance with these medications is hyperkalemia, not hyponatremia. 1

SIADH and Hyponatremia: The Rare Complication

Evidence for ACE Inhibitor-Induced SIADH

• ACE inhibitors can cause SIADH, but this is an uncommon adverse effect that presents with dilutional hyponatremia (serum sodium <135 mEq/L, often severe <120 mEq/L). 2, 3

• The mechanism involves ACE inhibitors blocking peripheral conversion of angiotensin I to angiotensin II, but not blocking this conversion in the brain. Increased circulating angiotensin I enters the brain, gets converted to angiotensin II centrally, and stimulates both thirst and inappropriate ADH release from the hypothalamus. 3

• This can occur at any time during therapy—not just at initiation—and may develop suddenly even after years of stable use when additional factors affecting water homeostasis are introduced (such as increased fluid intake, perioperative states, or liquid diets). 2

• Case reports document severe SIADH with lisinopril (serum sodium as low as 109 mEq/L) that resolved completely upon discontinuation of the ACE inhibitor. 3

Clinical Presentation of Drug-Induced SIADH

• Symptoms depend on the severity and rapidity of sodium decline: headaches, nausea, tingling sensations, confusion, and in severe cases, seizures. 3, 4

• Elderly patients are at particularly high risk for drug-induced SIADH due to age-related physiological changes including decreased total body water, impaired baroreceptor sensitivity, and altered ADH response. 5, 6

ARBs and SIADH

• The evidence base for ARBs causing SIADH is even more limited than for ACE inhibitors, with minimal published case reports. The theoretical mechanism would be similar but appears to occur less frequently in clinical practice. 6

Hyperkalemia: The Primary Electrolyte Concern

Incidence and Risk Factors

• Hyperkalemia is the predominant electrolyte disturbance with ACE inhibitors and ARBs, occurring in approximately 11% of outpatients on these medications. 7

• Moderate-dose ACE inhibitors (captopril 75 mg/day, enalapril 10 mg/day, or lisinopril 10 mg/day) are significantly associated with hyperkalemia development, particularly in patients with diabetes. 1

• Risk factors for hyperkalemia include: serum creatinine >136 μmol/L (1.5 mg/dL), blood urea nitrogen >6.4 mmol/L (18 mg/dL), congestive heart failure, diabetes mellitus, and age >70 years. 1, 7

Mechanism

• ACE inhibitors and ARBs reduce aldosterone secretion by blocking the renin-angiotensin-aldosterone system, leading to decreased renal potassium excretion and subsequent hyperkalemia. 1

• Hyperkalemia can be sufficiently severe to cause cardiac conduction disturbances, making this a potentially life-threatening complication. 1

Monitoring Requirements

The American Geriatrics Society provides explicit monitoring guidelines: 1

• Check renal function and serum potassium within 1 to 2 weeks of ACE inhibitor or ARB initiation
• Recheck with each dose increase
• Monitor at least yearly during maintenance therapy
• More frequent monitoring (every 2-4 weeks initially) is warranted in elderly patients with diabetes and chronic kidney disease 8

Management of Hyperkalemia

• For potassium 5.0-6.0 mEq/L: Reduce ACE inhibitor/ARB dose by 50% rather than complete discontinuation to maintain cardioprotective benefits. 8

• For potassium >6.0 mEq/L: Temporarily discontinue all RAAS inhibitors completely. 8

• Discontinue potassium supplements, potassium-sparing diuretics, and hold aldosterone antagonists temporarily. 8

• Implement dietary potassium restriction to <3 g/day (77 mEq/day). 8

Clinical Algorithm for Older Adults with Hyponatremia and Hyperkalemia

Initial Assessment

1. Verify the electrolyte abnormalities are real (not pseudohyperkalemia from hemolysis or lab error). 8

2. Obtain ECG immediately if potassium ≥5.6 mEq/L to assess for cardiac conduction abnormalities, as elderly patients are at higher risk for cardiotoxicity. 8

3. Calculate actual creatinine clearance—do not rely on serum creatinine alone in elderly patients, as age-related reductions in muscle mass can mask significant renal dysfunction. 1, 8

Medication Review

1. Review all medications for causes of both hyponatremia and hyperkalemia:
   • ACE inhibitors/ARBs can cause both (SIADH is rare; hyperkalemia is common)
   • Thiazide diuretics cause hyponatremia but typically cause hypokalemia 1
   • NSAIDs increase risk of both complications when combined with ACE inhibitors 1, 6

Management Strategy

1. For moderate hyponatremia (sodium 125-134 mEq/L) with mild hyperkalemia (potassium 5.0-5.5 mEq/L):

   • Reduce ACE inhibitor/ARB dose by 50% 8
   • Implement fluid restriction to 1000 mL/day for SIADH 3
   • Restrict dietary potassium to <3 g/day 8
   • Discontinue any potassium supplements or potassium-sparing diuretics 8

2. For severe hyponatremia (sodium <125 mEq/L) or severe hyperkalemia (potassium >6.0 mEq/L):

   • Discontinue ACE inhibitor/ARB completely 8, 3
   • Consider hospitalization for IV sodium chloride and/or furosemide therapy for symptomatic hyponatremia 6
   • Administer insulin 10 units IV with 25g dextrose for severe hyperkalemia 8

3. Recheck electrolytes within 24-72 hours after intervention, not at the standard 4-month interval. 8

Critical Pitfalls to Avoid

• Do not assume stable long-term ACE inhibitor/ARB therapy precludes new-onset SIADH—it can develop suddenly after years of use when additional factors (increased fluid intake, perioperative state, illness) are introduced. 2

• Do not completely discontinue ACE inhibitors/ARBs for mild hyperkalemia (5.0-5.5 mEq/L)—dose reduction is preferred to maintain cardioprotective and renoprotective benefits unless potassium exceeds 6.0 mEq/L. 8

• Do not combine ACE inhibitors with ARBs—this combination increases risk of hyperkalemia and hypotension without additional benefit and is contraindicated. 1

• Do not overlook concurrent medications that increase SIADH or hyperkalemia risk: NSAIDs, potassium-sparing diuretics, aldosterone antagonists, and potassium supplements. 1, 6

• In elderly patients, do not rely solely on serum creatinine to assess renal function—calculate actual creatinine clearance, as reduced muscle mass masks renal insufficiency. 1, 8