What is the interaction between Angiotensin-Converting Enzyme (ACE) inhibitors and lithium?

From the Guidelines

ACE inhibitors and lithium should not be used together without careful monitoring due to their potentially dangerous interaction, as it can lead to increased lithium blood levels and potentially life-threatening lithium toxicity. When considering the use of ACE inhibitors in patients taking lithium, it is crucial to weigh the benefits against the risks, prioritizing morbidity, mortality, and quality of life. The interaction between ACE inhibitors and lithium is not directly addressed in the provided evidence 1, which focuses on the use of ACE inhibitors in heart failure patients and their potential effects on renal function and hyperkalemia. However, the general principle of monitoring renal function and electrolyte levels when using ACE inhibitors can be applied to the context of lithium therapy.

According to the provided evidence 1, an increase in creatinine of up to 50% above baseline or a potassium level of ≤5.5 mmol/L is considered acceptable when using ACE inhibitors. Nevertheless, these guidelines do not directly translate to the management of lithium levels. In clinical practice, when ACE inhibitors are combined with lithium, lithium levels should be monitored frequently, initially on a weekly basis, and the lithium dose may need to be adjusted to prevent toxicity. Patients should be educated about the signs of lithium toxicity, such as tremor, confusion, and nausea, and instructed to seek immediate medical attention if these symptoms develop.

Given the potential risks associated with the concomitant use of ACE inhibitors and lithium, alternative antihypertensive medications may be considered for patients requiring lithium therapy. The decision to use ACE inhibitors in these patients should be made on a case-by-case basis, taking into account the individual's specific clinical needs and the potential benefits and risks of the treatment. In general, the use of ACE inhibitors in patients taking lithium requires close monitoring and careful management to minimize the risk of adverse interactions.

From the FDA Drug Label

Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs, which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon discontinuation of lithium and the ACE inhibitor. Monitor serum lithium levels during concurrent use. Caution should be used when lithium and diuretics or angiotensin converting enzyme (ACE) inhibitors are used concomitantly because sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity. When such combinations are used, the lithium dosage may need to be decreased, and more frequent monitoring of lithium plasma levels is recommended

The interaction between ACE inhibitors (such as lisinopril) and lithium can increase the risk of lithium toxicity due to decreased renal clearance of lithium. To minimize this risk, it is recommended to:

• Monitor serum lithium levels closely during concurrent use
• Consider decreasing the lithium dosage when used with ACE inhibitors
• Increase the frequency of lithium plasma level monitoring 2 3

From the Research

Ace Inhibitor and Lithium Interaction

The interaction between ace inhibitors and lithium is a significant concern due to the potential for increased lithium concentrations and toxicity.

• The mechanism of this interaction is thought to be related to the effect of ace inhibitors on renal function and electrolyte balance 4, 5.
• Studies have shown that the combination of lithium and ace inhibitors can lead to increased lithium concentrations, reduced lithium clearance, and increased risk of lithium toxicity 6, 5.
• Factors that may contribute to this interaction include age, renal function, and electrolyte balance, with elderly patients being uniquely predisposed to this interaction 5.
• It is recommended that renal function be closely monitored when patients on lithium treatment are given ace inhibitors, and that doses of both drugs be chosen with caution to avoid serious drug interaction 4.
• Additionally, lithium concentration should be controlled on a regular level when combining lithium with ace inhibitors, and sufficient hydration should be ensured to minimize the risk of lithium intoxication 6.

Clinical Relevance

The clinical relevance of this interaction is significant, as lithium has a narrow therapeutic range and relatively minor increases in serum concentrations can induce serious adverse sequelae 7.

• Concomitant use of diuretics, particularly thiazide diuretics, has been associated with an increased risk of lithium toxicity, and ace inhibitors may also impair lithium elimination 7.
• Other medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antipsychotics, anticonvulsants, and calcium antagonists, have also been implicated in case reports of lithium toxicity, although the relative risk of serious interactions appears to be low 7.
• Therefore, caution is advised when combining lithium with any of these medications, and regular monitoring of lithium concentrations and renal function is recommended 6, 5, 7.