When it comes to Lithium, you can (thankfully) forget all about the P450 enzymes, because they don’t touch this salt. Lithium enters the bloodstream, accomplishes its mysterious mood-stabilizing duties, and then is simply whisked out of the body intact by the kidneys via urine. So with Lithium, it’s all about kidneys.

There’s only one common way for Lithium levels to be decreased, and that’s through caffeine intake. Caffeine increases the glomerular filtration rate, causing us to urinate more, leading to indiscriminate losses of solutes, including Lithium.

More to the point though, there are several ways for the kidney to get fooled into retaining too much Lithium. These three drug interactions should be committed to memory:

1. NSAIDs. This includes every drug in the non-steroidal anti-inflammatory drug category except Aspirin and Clinoril (sulindac). If you have a patient on Lithium who is taking significant ongoing doses of ibuprofen (Motrin, Advil), indomethicin (Indocin), naproxen (Naprosyn, Alleve), or even the new Cox-2 inhibitors such as Vioxx or Celebrex, you’d better be more aggressive about monitoring Lithium levels, which can double. The mechanism is not entirely clear, but may relate to the inhibition of prostaglandins leading to interference with Lithium excretion.

2. Hydrochlorothiazide. This common diuretic treats hypertension by increasing Na (sodium) excretion in the distal tubule of the kidney, leading to increased urination, decreased total body water, and therefore decreased blood pressure. The kidney doesn’t particularly like to see such havoc being played with its fine-tuned homeostatic mechanism, and actively tries to compensate for the loss of Na by retaining it elsewhere. But Na is very similar to Lithium (Li), and in snatching back up as much Na as it can, the kidney indiscriminately snatches up a lot of Li, causing an increase of up to 40% in Li levels.

3. ACE inhibitors (eg, lisinopril, enalapril, and captopril). These blood pressure medications work by inhibiting ACE (Angiotensin Converting Enzyme), which normally converts Angiotensin I to Angiotensin II.

Angiotensin II (A-II) is a great molecule if you like vasoconstriction, but if your blood pressure is high, you prefer ACE inhibition, which prevents too much A-II from being created. So how is all this related to Lithium? A-II also promotes the release of aldosterone, which causes the kidney to retain Na. If you lower A-II, you lower aldosterone, and limit the kidney’s ability to retain Na. And, just as in hydrochlorothiazide (above), the kidney compensates by conserving Na in other ways, confuses Li for Na, and you get high levels of Li.

As an aside, both dehydration and low sodium diets can increase Lithium levels, by mechanisms similar to those discussed above: in both cases, the kidneys trying to hold onto sodium. So advise your sun-loving and diet-following patients accordingly.

Bottom line: With your Lithium-treated patients, remember the big three of Lithium toxicity: NSAIDs, ACE-inhibitors, and Hydrochlorothiazide. The TCR mnemonic is: “With Lithium, No ACE in the Hole.” Monitor Li levels carefully when any of these are present.

TCR VERDICT: Lithium Mnemonic: No ACE in the Hole