Concomitant Lithium and ACEIs: Increase the Index of Suspicion for Lithium Toxicity

Benjamin T. Duhart Jr, MS, PharmD, and Timothy H. Self, PharmD

Volume 57 - Issue 3 - March 2017

Lithium products, commonly prescribed for bipolar disorder, have a narrow therapeutic index, and therapeutic drug monitoring is used to maintain serum concentrations within the therapeutic range (0.6-1.5 mEq/L). Lithium levels above 1.5 mEq/L can contribute to the development of lithium toxicity.1 The initial signs and symptoms can include nausea, abdominal pain, vomiting, diarrhea, fatigue, drowsiness, lethargy, confusion, and tremor. If untreated, lithium toxicity can progress to coma, seizures, ataxia, and renal insufficiency.2 Approximately 1 of 100 patients per year receiving lithium experience moderate to severe lithium intoxication.3

Lithium is primarily excreted via the kidneys, so changes in the estimated glomerular filtration rate will affect lithium levels accordingly. The concomitant use of lithium and other medications, particularly angiotensin-converting enzyme inhibitors (ACEIs), has been associated with the development of lithium toxicity. The interaction between lithium and enalapril was first reported in 1986,4 and reports of lithium toxicity with concomitant use of other ACEIs have subsequently been cited.5-11

The onset of the interaction is delayed, and lithium toxicity may result within days or weeks after coadministration of lithium and ACEIs.9 Multiple mechanisms for the lithium-ACEI interaction have been proposed. Inhibition of ACE leads to a decrease in the concentration of angiotensin II, which is responsible for the reabsorption of sodium and water in the proximal tubules and stimulates aldosterone production.9 Molecularly, lithium resembles sodium; approximately 60% of lithium is reabsorbed in the proximal tubules and 20% between the loop of Henle and the collecting ducts.1,12 Lithium is transported primarily via the sodium-hydrogen exchanger in the proximal tubules and the sodium channel system in the collecting ducts.1

Furthermore, lithium has been associated with the development of kidney injury. Nephrogenic diabetes insipidus is considered an acute adverse effect of lithium therapy. Amiloride has been successfully used to treat nephrogenic diabetes insipidus.13 Chronic lithium use also may cause chronic tubulointerstitial nephropathy, which is associated with the development of chronic kidney disease and is irreversible.14 Recently, one group of authors evaluated the effects of long-term lithium use and noted that approximately 40% of patients had a decrease in glomerular function over time.15 Early detection is necessary in order to prevent progression to end-stage kidney disease.14

A high index of suspicion for lithium toxicity is necessary when it is taken concomitantly with ACEIs. The evaluation of risk factors associated with lithium toxicity (eg, elderly,10 volume-depleted,11 chronic kidney disease11) and therapeutic drug monitoring are necessary in order to prevent the interaction. If concomitant administration of lithium and ACEIs is necessary, closely monitoring levels and, if possible, decreasing the lithium dose to prevent lithium intoxication are recommended.

Benjamin T. Duhart Jr, MS, PharmD, is an associate professor of clinical pharmacy at the University of Tennessee Health Science Center and a clinical pharmacy specialist at Methodist University Hospital in Memphis, Tennessee.

Timothy H. Self, PharmD, is a professor of clinical pharmacy at the University of Tennessee Health Science Center and program director of the Postgraduate Year 2 Internal Medicine Pharmacy Residency at Methodist University Hospital in Memphis, Tennessee.

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