This decreases solute-free water clearance leading to the development of hyponatremia (Fig. 1B). Drugs such as tolvaptan by binding see more to the V2 receptor block the effect of AVP resulting in an increase in solute-free water clearance and correction of the hyponatremia (Fig. 1C). In addition, this group of drugs causes a mild natriuresis,

increases urine output, and causes more rapid weight loss compared to patients not receiving the drug.10, 11 Tolvaptan (Samsca, Otsuka America Pharmaceutical, Inc, Tokyo, Japan) was recently approved by the FDA for the treatment of hyponatremia in patients with cirrhosis. This approval was based on two randomized controlled trials comparing placebo to tolvaptan in patients with hyponatremia.11 The majority of the patients in the studies suffered from congestive heart failure; there were only 63 patients with cirrhosis who received tolvaptan. Patients with a Child-Pugh score of >10 or sodium >120 mmol/L were excluded. Patients were treated for up to 30 days

and during the first 4 days the dose of tolvaptan could be increased depending upon the response to treatment. Serum sodium rose quickly in those receiving tolvaptan and was ≥135 mmol/L by day 20. Discontinuation of the treatment was associated with a fall in serum sodium. No mention is made of the use of diuretics in this group of patients.11 The adverse events seen with tolvaptan are shown in Table 1. There was no mention of the adverse events in patients with congestive heart failure versus cirrhosis except for the increase risk of gastro-intestinal bleeding in patients with p38 MAPK signaling cirrhosis receiving tolvaptan. This issue was discussed during the FDA review of tolvaptan and the increased risk of bleeding may be due to the effect of tolvaptan on vitamin K dependent clotting factors and platelet function.12 No difference in survival was seen with tolvaptan

vs. placebo but the patients were treated for a maximum of only 30 days. However in a longer study of up to one year the use of another vasopressin V2 antagonist, satavaptan, in combination with diuretics was associated with an increase in mortality compared to placebo leading to withdrawal of the drug 上海皓元 by the pharmaceutical company Sanofi-Aventis. Somewhat more variceal bleeding was observed in those receiving satavaptan but other adverse events occurred at the same frequency in treated vs. control groups. The reason for an increase in death rate in those receiving satavaptan appeared to be due to a more frequent fatal outcome with a particular adverse event.13 The adverse event most feared in the use of these drugs is a too rapid rise in serum sodium (>12 mmol/L/24 hours) leading to hypernatremia, osmotic demyelination and CNS injury. In the long term study with satavaptan, 9.5% of patients had a serum sodium of >145 mmol/L.