Tolvaptan Hyponatremia

The potent antidiuretic hormone AVP orchestrates the regulation of free water absorption, body fluid osmolality, cell contraction, blood volume, and blood pressure through stimulation of three G-protein-coupled receptor subtypes Vi-vascular types a and b, V2-renal, and V3-pituitary. Increased AVP secretion is the trademark of several pathophysiological disorders, including heart failure, impaired renal function, liver cirrhosis, and SIADH. As a consequence, these patients experience excess water retention or inadequate free-water excretion, which results in the dilution of sodium concentrations, frequently manifesting as clinical hyponatremia (serum sodium concentration 135mmol/L). This electrolyte imbalance increases mortality rates by 60-fold. Selective antagonism of the AVP V2 receptor promotes water 

---

A group of nonpeptide antagonists of vasopressin receptors is being investigated for use in patients with hyponatremia or acute heart failure, which is often associated with elevated concentrations of vasopressin. Conivaptan has high affinity for both Vla and V2 receptors. Tolvaptan has a 30-fold higher affinity for V2 than for Vi receptors. In several clinical trials,... 

Non-peptide vasopressin receptor antagonists include relcovaptan (an antagonist at Vla receptors), lixivaptan, satavaptan, and tolvaptan (V2), and conivaptan (mixed Via/v2)- They have been used in the treatment of hyponatremia. 

In a double-blind placebo-controlled study of the effects of three doses of tolvaptan (30, 45, or 60 mg/day) in 254 patients with chronic heart failure taking stable doses of furosemide there were significant reductions in body weight and increased urine volumes edema improved and serum sodium normalized in those with hyponatremia (5). There were no significant changes in heart rate, blood pressure, serum potassium, or renal function. 

In two multicenter, randomized, double-blind, placebo-controlled studies of tolvaptan in 448 patients with euvolemic or hypervolemic hyponatremia, tolvaptan 15-60 mg/day increased serum sodium concentrations significantly compared with placebo (6). The main adverse effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. 

In a multicenter randomized, double-blind, placebo-controlled study in 4133 patients with heart failure, tolvaptan 30 mg/day for a minimum of 60 days in addition to standard therapy significantly improved dyspnea, body weight, and edema in patients with hyponatremia, serum sodium concentrations increased significantly (7). The main adverse effects were increased thirst and a dry mouth. 

Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006 355(20) 2099-112. 

As Of 2009, conivaptan HCl (1) is one of three vasopressin receptor antagonists approved for use in the treatment of hyponatremia worldwide. The U.S. approval of 1 was preceded by the 2006 approval of mozavaptan hydrochloride (2) in Japan. In 2009, tolvaptan (3) joined 1 as an FDA-approved agent for the treatment of hyponatremia. In this chapter, the pharmacological profile and synthesis of conivaptan hydrochloride (1) is examined in detail. 

Observational studies The use of tolvaptan in short- and long-term studies in heart failure and hyponatremia has been reviewed [82 ]. In an open extension study in 4133 patients with heart failure who were followed for a mean of 10 months, 111 patients with hyponatremia took oral tolvaptan for a mean of 701 days dry mouth, thirst, and hypernatremia were more common in those who took tolvaptan the incidences of hypotension and renal failure were comparable in the two groups [83 ]. The most common adverse events that were assessed by the investigator as being potentially related to the use of tolvaptan were pollakiuria ( = 11) thirst (n = 10) fatigue (n = 6) and dry mouth, polydipsia, polyuria, hypotension, hypernatremia, dizziness, headache, peripheral edema, and acute renal failure (four patients each) [84 ]. 

Berl T, Ouittnat-Pelletier F, Verbalis JG, Schrier RW, Bichet DG, Ouyang J, Czerwiec FS SALTWATER Investigators Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010 21(4) 705-12. 

In two randomized placebo-controlled trials of tolvaptan 15-60 mg in patients with either euvolemic or hypervolemic hyponatremia, adverse events were similar to those with placebo [43 ]. The most common adverse reactions were thirst (14% versus 5%) and dry mouth (13% versus 4%). Death rates were similar 14 of 223 patients who took tolvaptan compared with 13 of 220 patients who took placebo. Four patients who took tolvaptan had an increased serum sodium concentration to over 146 mmol/1, and in four patients the rate of increase of sodium was more rapid than clinically appropriate. Close moiutor-ing of serum sodium concentrations and plasma volume status is essential. Fluid restriction is not required. Polyuria is common. 

Tolvaptan, 4 -[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-lH-l-benzazepin-l-yl) carbonylj-o-tolu-m-toluidide, has been approved by the FDA and EMA for management of hyponatremia. It is taken orally in a dose of 15 mg/day and is titrated to a maximum of 60 mg, depending on sodium concentrations and volume status. Tolvaptan is metabolized by the liver. Blood concentrations of tolvaptan are increased when it is co-admin-istered with CYP3A4 inhibitors such as dil-tiazem, ketoconazole, and grapefruit juice, and reduced when it is co-administered with CYP3A4 inducers such as rifampicin. 

Gheorghiade M, Gottlieb SS, Udelson JE, Konstam MA, Czerwiec F, Ouyang J, Orlandi C. Tolvaptan investigators. Vasopressin V2 receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia. Am J Cardiol 2006 97 1064-7. 

Cardenas A, Gines P, Marotta P, Czerwiec F, Oyuang J, Guevara M, et al. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J Hepatol 2012 56(3) 571-8. 

---