A 45-year-old woman with bipolar I disorder on lithium has a serum level of 0.8 mEq/L. She is started on ibuprofen 400 mg TDS for knee pain. Two weeks later she presents with coarse tremor, ataxia, and confusion. Her lithium level is now 2.4 mEq/L. What is the mechanism of this interaction?

• A NSAIDs inhibit hepatic lithium metabolism via CYP3A4
• B NSAIDs displace lithium from protein binding sites
• C Ibuprofen blocks active tubular secretion of lithium
• D NSAIDs reduce renal prostaglandin synthesis, decreasing lithium clearance ✓

Explanation

Lithium is excreted entirely by the kidneys; it is not metabolized. NSAIDs inhibit prostaglandin synthesis, leading to renal afferent arteriolar vasoconstriction, reduced GFR, and enhanced proximal tubular reabsorption of lithium (sodium and lithium share reabsorption pathways). This raises lithium levels significantly. The same mechanism applies to COX-2 inhibitors. Lithium is not protein-bound. This interaction is clinically critical — lithium toxicity at levels >2 mEq/L can cause permanent neurological damage.

Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.

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