Lithium interferes with the production of an important metabolic regulator called cAMP which is part of the molecular sequence that leads to the ability of the kidney to concentrate urine. Normally, AQP2s allow these cell membranes to let much more water than usual flow through them, which is how the kidneys are able to reabsorb water and concentrate urine. If the AQP2s cannot reach the cell membranes, the kidneys are not able to perform these functions. Several reports mention that indomethacin therapy helps reduce NDI-related polyuria since it seems to inhibit prostaglandin synthesis, which, in turn, would allow for more cAMP production. However, indomethacin can promote lithium toxicity .
Hydrochlorothiazide helps decrease extracellular fluid volume and stimulate fluid reabsorption.
This reduces the amount of fluid that part of the kidney has to deal with. It must be used carefully because it too, can lead to lithium toxicity. The authors recommend administering lower lithium levels to the elderly and monitoring them for NDI and lithium toxicity.