Although the mechanism is not completely understood, previous case reports hypothesized that ACE inhibitor therapy can lead to Syndrome of Inappropriate Antidiuretic Hormone (SIADH).1,3 Angiotensin I is not converted to angiotensin II peripherally with ACE inhibitor therapy. This elevated circulating level of angiotensin I is available to cross the blood-brain barrier where it is converted to angiotensin II. Angiotensin can then stimulate vasopressin release, which, in turn, increases thirst and leads to decreased amounts of concentrated urine.4 The combination of increased thirst and concentrated urine can lead to hyponatremia.
The clinical manifestations of hyponatremia can vary. In patients with ACE inhibitor-induced hyponatremia, an early sign may be polydipsia. Once hyponatremia develops, patients may experience nausea, muscle spasms or weakness, and general malaise. Additionally, lethargy, a decreased level of consciousness, and headaches may occur. In the most severe cases, hyponatremia may lead to seizures, coma, and eventually death.
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Several case reports involving various ACE inhibitors, such as captopril, enalapril, and lisinopril, have been reported over the past 30 years, citing the connection linking these medications to SIADH and symptomatic hyponatremia. A large number of cases involved patients with established congestive heart failure for whom ACE inhibitors were added because of their beneficial impact on improved survival and reduced left ventricular dysfunction.5 Angiotensin converting enzyme inhibitor-induced hyponatremia may be confounded by heart failure, due to the complex disease pathophysiology.1 Therefore, case reports of ACE inhibitors use in patients treated for indications other than heart failure, such as hypertension, provide a clearer picture of ACE inhibitor-induced hyponatremia.
One such striking case report involved a 63-year-old woman taking lisinopril 10 mg daily as monotherapy (no other medications) for mild hypertension with a baseline serum sodium level within normal limits.6 One month later, the patient was admitted a with serum sodium level of 101 mEq/L and symptomatic with altered mental status and generalized tonic-clonic seizures. Once the serum sodium was corrected, the patient’s mental status improved, and her 1-year follow-up examination was unremarkable. This case report is significant for its findings that there may be a cause-and-effect relationship between lisinopril monotherapy and symptomatic hyponatremia that occurred within a month. There are cases of hyponatremia in patients receiving ACE inhibitor therapy in addition to established diuretic therapy. For example, a woman aged 71 years was admitted for elevated BP with an initial medication regimen that included HCTZ and other antihypertensive medications.7 She was given captopril at increasing doses up to 150 mg daily. The patient’s serum sodium levels dropped correspondingly with titrated doses of captopril. The patient reported feeling confusion, and her serum sodium levels dropped to 114 mEq/L. Once captopril was discontinued and serum sodium corrected with IV fluids, the patient’s confusion subsided. The patient was discharged on a medication regimen that continued HCTZ but not the ACE inhibitor, with no clinical consequences and normal serum sodium levels over the following year. Similarly, the patient in this case study had established HCTZ therapy with normal serum sodium that declined upon addition of an ACE inhibitor.
Other factors that could contribute to hyponatremia, such as beer potomania, confound the current case of hyponatremia. This patient reported chronic beer ingestion, which can lead to hyponatremia and may have aggravated the hyponatremia upon initiation of lisinopril. Additionally, the patient was taking HCTZ, an agent known to cause hyponatremia, prior to initiation of the ACE inhibitor. Another limiting factor noted was that serum magnesium levels were not measured to assess for potential hypomagnesemia, which may affect other electrolytes.
Using the Naranjo Assessment scale, a score of 3 was calculated, indicating a possible link to lisinopril as the cause of hyponatremia.8 Although the patient had the aforementioned risk factors, the notable drop of serum sodium level correlated with the lisinopril administration, which was previously stable despite HCTZ treatment and alcohol consumption. The time line of events led the authors to believe that hyponatremia was strongly related to lisinopril. This patient was fortunate that he experienced no neurologic complications, which have been reported in other cases of ACE inhibitor-induced hyponatremia, manifested from the drop in serum sodium.
Conclusion
Though rarely occurring, hyponatremia should be considered a potentially serious AE associated with ACE inhibitor therapy. Timely monitoring of electrolytes, BUN, and SCr should continue to assess for more common AEs of elevated SCr and hyperkalemia, but clinicians should be aware of the potential for ACE inhibitor-induced hyponatremia.