Why Patients Taking Lisinopril Should Avoid Lithium
Patients taking lisinopril are advised to avoid lithium because ACE inhibitors like lisinopril reduce the renal clearance of lithium by causing sodium loss, which leads to increased serum lithium levels and a significant risk of lithium toxicity. 1
Mechanism of the Drug Interaction
The interaction occurs through a well-defined pharmacokinetic mechanism:
- ACE inhibitors cause sodium loss, which directly reduces renal lithium clearance, leading to elevated and potentially toxic lithium levels 1
- Lithium is primarily excreted by the kidneys, and its clearance is proportional to plasma concentration—any factor that impairs renal excretion increases toxicity risk 1
- The FDA drug label explicitly warns that "sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity" when lithium and ACE inhibitors are used together 1
Clinical Evidence of Toxicity Risk
Multiple case reports document serious lithium toxicity when ACE inhibitors are combined with lithium:
- A documented case showed a five-fold increase in serum lithium levels (from therapeutic to 3.4 mEq/L) after switching from fosinopril to lisinopril, with the patient requiring hospitalization and IV hydration 2
- Another case report described lithium toxicity specifically when lisinopril was substituted for another antihypertensive agent 3
- These toxicity events can occur several weeks after initiating the combination, making them particularly dangerous 2
Clinical Manifestations of Lithium Toxicity
Early recognition of toxicity is critical:
- Early signs include tremor, nausea, diarrhea, and polyuria-polydipsia 4
- More severe toxicity manifests as confusion, ataxia, drowsiness, muscular weakness, and seizures 1, 5
- Chronic lithium poisoning can result in prolonged hospitalization due to impaired mobility and cognition, and rarely, persistent neurological deficits (particularly cerebellar) 5
When Combination Therapy Cannot Be Avoided
If the combination is absolutely necessary due to life-threatening psychiatric indications:
- The lithium dosage must be decreased when ACE inhibitors are initiated 1
- Implement aggressive serum lithium monitoring—check levels 1-2 weeks after adding the ACE inhibitor or making dose adjustments 6, 3
- Ensure adequate hydration (2500-3000 mL daily) and normal salt intake 1
- Avoid concurrent use of hydrochlorothiazide or other diuretics, as this combination dramatically increases toxicity risk 7
- Monitor renal function closely, as patients with reduced kidney function (GFR <60 mL/min/1.73 m²) require even more frequent monitoring 6
Important Clinical Pitfalls
Several factors compound the risk:
- Dehydration from any cause (sweating, diarrhea, fever) further reduces lithium clearance and necessitates temporary dose reduction or cessation 1, 8
- Older patients and those with baseline renal impairment are at highest risk and require the most vigilant monitoring 2
- The FDA explicitly states that lithium "should generally not be given to patients receiving diuretics" due to the very high risk of toxicity 1