What happens when you take lithium with ace inhibitors?
ACE inhibitors (lisinopril, enalapril, ramipril, perindopril, benazepril, captopril, and others) block the conversion of angiotensin I to angiotensin II. This lowers blood pressure and protects the kidneys in diabetes and heart failure, but it also reduces angiotensin II's effect on the efferent arteriole of the glomerulus. The result is a small but consistent drop in glomerular filtration rate and a fall in aldosterone-driven sodium reabsorption.
Lithium is cleared almost entirely by the kidneys without metabolism. Its reabsorption competes with sodium in the proximal tubule. When ACE inhibitors lower GFR and shift sodium handling, the kidneys reabsorb more lithium, and serum lithium levels rise. A pooled analysis estimates an average serum lithium increase of about 36 percent with ACE inhibitor co-therapy, and the effect can be larger in older patients, dehydrated patients, or patients with chronic kidney disease.
A distinctive and dangerous feature of this interaction is its delayed onset. Toxicity does not always appear in the first week. Multiple published case reports document lithium toxicity emerging 3 to 5 weeks after starting an ACE inhibitor. A patient who tolerated the new blood pressure pill at first may decompensate later, sometimes with acute kidney injury and severe lithium toxicity.
Why is this important?
Lithium has a narrow therapeutic index, and a 36 percent rise from a baseline of 0.8 mEq/L pushes the level to 1.1 mEq/L, which is acceptable. From a baseline of 1.0 mEq/L it rises to 1.36 mEq/L, which approaches the side-effect range. Cases in the literature describe creatinine rising from 0.87 to 2.2 mg/dL and lithium climbing from 0.8 to 2.0 mEq/L within weeks of starting lisinopril, with confusion, tremor, and nausea.
Some clinicians, including the authors of widely used psychiatric pharmacology references, recommend simply not combining ACE inhibitors with lithium when alternatives exist. The Lithium Handbook describes lisinopril as the only medication that "should not be combined with lithium." In real-world practice, the combination is sometimes unavoidable (for example, in patients with diabetic nephropathy or heart failure), but it requires careful monitoring.
Angiotensin II receptor blockers (ARBs) such as losartan and valsartan share a similar but somewhat weaker mechanism and also raise lithium levels. The same warning applies to them, particularly in older adults.
What should you do?
- If you have bipolar disorder or are on lithium and your blood pressure needs treatment, tell every prescriber about your lithium therapy so they can consider alternatives such as calcium channel blockers (amlodipine, nifedipine) or low-dose beta-blockers.
- If an ACE inhibitor is the best choice for your kidneys or heart, the prescriber should plan monitoring: baseline lithium, creatinine, and electrolytes, repeat at 1 to 2 weeks, again at 4 to 6 weeks, and after any dose change.
- Avoid combining ACE inhibitors, NSAIDs, and lithium together. This triple combination dramatically increases the risk of acute kidney injury and severe lithium toxicity.
- Stay hydrated, particularly in hot weather or during illness.
- Recognize the symptoms of lithium toxicity: tremor, nausea, vomiting, diarrhea, confusion, slurred speech, ataxia. Seek medical care promptly.
Which specific products are affected?
Affected ACE inhibitors include lisinopril (Zestril, Prinivil), enalapril (Vasotec), ramipril (Altace), benazepril (Lotensin), captopril (Capoten), perindopril (Aceon), trandolapril (Mavik), fosinopril (Monopril), quinapril (Accupril), and moexipril (Univasc), and combination products that contain them with hydrochlorothiazide. ARBs such as losartan (Cozaar), valsartan (Diovan), olmesartan (Benicar), telmisartan (Micardis), candesartan (Atacand), and irbesartan (Avapro) share a similar interaction profile.
The interaction applies to all lithium products: lithium carbonate (Eskalith, Lithobid, generic) immediate- and extended-release, and lithium citrate liquid.
The bottom line
ACE inhibitors raise lithium levels by reducing kidney clearance, and the effect can be delayed by weeks. When possible, choose a different class of antihypertensive in patients on lithium. When the ACE inhibitor is needed, the prescriber must plan for ongoing monitoring of lithium and creatinine, and patients should know the signs of lithium toxicity and report them promptly.