Review Question - QID 203739

Lithium is excreted largely unchanged by the kidneys and so is dependent on glomerular filtration for clearance. Any drug that decreases glomerular filtration including ACE inhibitors, NSAIDs, and diuretics (through dehydration) can cause lithium toxicity.

Lithium toxicity manifests as altered mental status, coarse tremors, convulsions, and death. For this reason, clinicians need to regularly monitor blood levels of lithium. Other side effects include fine tremor, renal failure, nephrogenic diabetes insipidus, GI disturbance, weight gain, hypothyroidism, and benign leukocytosis. In pregnancy, lithium can cause Ebstein's anomaly in the fetus. This cardiac defect appears as a displaced tricuspid valve towards the apex of the heart resulting in a larger right atrium and a smaller functional right ventricle. Ebstein's anomaly is shown in Illustration B.

Price et al. review bipolar disorder and emphasize the importance of monitoring lithium levels frequently early on (every one to two weeks after initiation) and before and after dosage changes. In addition, they recommend to monitor thyroid and renal function every two to three months for the first 6 months and 1-2 times a year, thereafter.

Rej et al. discuss lithium therapy and renal function and report the rate of acute renal failure with lithium therapy was increased with concomitant use of ACE-inhibitors or loop diuretics. The prevalence of chronic renal insufficiency ranged widely and risk factors included age, previous lithium toxicity, polyuria, and previously impaired kidney function.

Illustration A shows how various drugs can affect lithium levels. Illustration B is a pathologic specimen side-by-side with an ultrasound image of Ebstein's anomaly. Abbreviations: RA: Right atrium; ARV: Atrialized right ventricle; FRV: Functional right ventricle; AL: Anterior leaflet; SL: Septal leaflet; LA: Left atrium; LV: Left ventricle.

Incorrect answers:
Answer 1: Although insulin also partially relies on the kidney for clearance, increasing insulin dosage will not result in lithium toxicity.
Answers 3 & 4: Gemfibrozil and atorvastatin do not affect glomerular filtration significantly, and so will not result in lithium toxicity.
Answer 5: Warfarin is notorious for drug-drug interactions due to its reliance on the CYP450 system for metabolism. However, lithium is not metabolized by the liver and warfarin does not affect glomerular filtration so the interaction between these two drugs is minimal.