Hyponatremia is frequently encountered in clinical practice and usually induced by renal water retention. Many medications are considered to be among the various causes of
hyponatremia, because they either stimulate the release of
arginine vasopressin (AVP) or potentiate its action in the kidney.
Antidepressants,
anticonvulsants,
antipsychotics,
diuretics, and
cytotoxic agents are the major causes of
drug-induced
hyponatremia. However, studies addressing the potential of these drugs to increase AVP release from the posterior pituitary gland or enhance urine concentration through intrarenal mechanisms are lacking. We previously showed that in the absence of AVP,
sertraline,
carbamazepine,
haloperidol, and
cyclophosphamide each increased
vasopressin V2 receptor (V2R)
mRNA and
aquaporin-2 (
AQP2) protein and
mRNA expression in primary cultured inner medullary collecting duct cells. The upregulation of AQP2 was blocked by the V2R antagonist
tolvaptan or
protein kinase A (PKA) inhibitors. These findings led us to conclude that the
nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is the main mechanism of
drug-induced
hyponatremia. Previous studies have also shown that the V2R has a role in
chlorpropamide-induced
hyponatremia. Several other agents, including
metformin and
statins, have been found to induce antidiuresis and AQP2 upregulation through various V2R-independent pathways in animal experiments but are not associated with
hyponatremia despite being frequently used clinically. In brief,
drug-induced
hyponatremia can be largely explained by AQP2 upregulation from V2R-cAMP-PKA signaling in the absence of AVP stimulation. This paper reviews the central and nephrogenic mechanisms of
drug-induced
hyponatremia and discusses the importance of the canonical pathway of AQP2 upregulation in
drug-induced NSIAD.