DISCOVERY OF VASOPRESSIN

An interesting discovery study was reported in the year 1985 on the secretion from the pituitary gland that not only raises blood pressure,¹⁾ but also reduces urine production.²⁾ This substance is synthesized in the anterior hypothalamus and is secreted into the posterior pituitary and named as vasopressin.³⁾ Purification of vasopressin and identification of its amino acid⁴⁾ was followed by isolation of the gene and molecular cloning of its receptors: V_1a, V_1b, and V₂.⁵⁾⁶⁾ The V_1a receptor is found in smooth muscle, myocardium, hepatocytes, platelets, and brain, resulting in vasoconstriction, myocardial hypertrophy, glycogenolysis, and platelet aggregation. The V_1b receptor is associated with the secretion of corticotropin. The V₂ receptor is located in the collecting duct cells that results in repositioning of the water channel to the apical cell membrane.⁷⁾

HYPONATREMIA IN PATIENTS WITH HEART FAILURE

Hyponatremia in patients with heart failure (HF) is common and is associated with an increased risk of morbidity and mortality.⁸⁾ It is caused by multifactorial reasons, but primarily from decreased cardiac output, which increases the level of vasopressin. The increased production of vasopressin is either due to decreased circulating volume in the artery, which stimulates the arterial baroreceptor, or by dysregulation that elevates the level of vasopressin despite arterial distension, increased blood volume, and low plasma osmolality.⁹⁾ In patients with HF, increased vasopressin level especially affects the V_1a and V₂ receptors. The activation of V₂ receptor causes reabsorption of free water from the renal collecting ducts, and that of V_1a receptor causes vasoconstriction to raise blood pressure.¹⁰⁾ The mechanism of action of vasopressin via V₂ receptor in hyponatremia is worth describing in detail. When vasopressin combines with the vasopressin receptor of the collecting ducts, the activated receptor stimulates adenylyl cyclase to generate cyclic adenosine monophosphate (AMP); cyclic AMP activates protein kinase A, which is an enzyme that phosphorylates the aquaporin water channels. After phosphorylation, aquaporin translocates from the inside of the cell to the surface membrane of the collecting ducts. It then reabsorbs free water from the lumen of the collecting duct back into capillaries, thereby resulting in more concentrated urine in the collecting ducts and increase in free water in the body, and subsequently a lower serum concentration of sodium.³⁾ Despite the prevalence and clinical implication of hyponatremia in patients with HF, established therapies such as hypertonic saline, loop diuretics, and fluid restriction have several limitations including inadequate blood volume status, electrolyte imbalance, and compliance issues.¹¹⁾ Therefore, the use of vasopressin receptor (V₂) antagonist as a treatment strategy might have potential in regulating free water in patients with HF.

TOLVAPTAN, VASOPRESSIN RECEPTOR ANTAGONIST

Tolvaptan is a vasopressin receptor antagonist that inhibits the V₂ receptor and results in the suppression of reabsorption of free water, causing excretion of diluted urine and therefore, concentration of sodium in the blood increases.³⁾ The efficacy and safety of tolvaptan were evaluated in previous trials, including that in the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT trial),¹²⁾ Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST trial),¹³⁾ and Safety and sodium Assessment of Long-term Tolvaptan With hyponatremia: A year-long, open-label Trial to gain Experience under Realworld conditions (SALTWATER study).¹⁴⁾ In 2006, Schrier et al.¹²⁾ reported a multicenter randomized study comparing the efficacy of tolvaptan to placebo in patients with euvolemic or hypervolemic hyponatremia: serum sodium <135 mmol/L (SALT trial). Patients involved in the study had syndrome of inappropriate antidiuretic hormone secretion (SIADH), cirrhosis, or chronic HF in association with hyponatremia ¹². Primary endpoints were change in the average under the curve (AUC) for the serum sodium concentration from baseline to day 4, and the change from; both the endpoints were achieved without significant side effects. However, hyponatremia recurred during the week after discontinuation of tolvaptan on day 30.¹²⁾ Continually, tolvaptan was evaluated in larger number of patients for a longer duration (median follow-up of 9.9 months), who were hospitalized due to HF in 2007 (EVEREST trial).¹³⁾ The EVEREST trial was an event-driven randomized controlled study in which the primary outcome was a composite of all-cause mortality, cardiovascular death, and HF hospitalizations. Although tolvaptan did not improve HF-related morbidity and long-term mortality rates associated with acute HF syndrome, the serum sodium level increased significantly. Conforming to these results, tolvaptan was approved by the Food and Drug Administration (FDA) in 2009 for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. Later, in 2010, Berl et al.¹⁴⁾ conducted an open-label extension study of the SALT trial. This SALTWATER trial demonstrated the maintenance of serum sodium concentration with prolonged administration of tolvaptan in patients with chronic hyponatremia, with an acceptable safety.¹⁴⁾

Hence, tolvaptan may effectively increase the level of serum sodium without improving longterm outcomes. Tolvaptan can be considered for regulating free water in the body in patients with hyponatremia and HF, without survival benefit. Compared to other diuretics, especially the most commonly used loop diuretics, tolvaptan only releases free water into the collecting ducts, but loop diuretics create a diuretic effect by inhibiting the Na-K-2Cl symporters in the ascending limb of the loop of Henle.¹⁵⁾ The mechanism of action of loop diuretics can cause diuretic resistance, renal dysfunction, and electrolyte imbalance. Moreover, one study discovered that the use of loop diuretics reduced renal blood flow to a greater extent than that did tolvaptan.¹⁶⁾ Therefore, despite the lack of survival benefit, tolvaptan can be considered an effective treatment in patients with hyponatremia and HF due to the advantages of its specific mechanism.

USE OF TOLVAPTAN

Tolvaptan has a half-life of 6–8 hours and maximum effect at 2 hours after administration. Metabolism is mainly carried out by the cytochrome P-450 isoenzyme CYP3A4 present in liver, and the amount of excretion in urine is less than 5%.³⁾ The initial recommended dose is 15 mg per day, and if necessary, the dose can be increased up to 60 mg per day at intervals of 24 hours or more, depending on the serum sodium concentration. Drug titration is better to be performed while the patient is being hospitalized, since it is necessary to check the initial serum sodium level concentration for drug dosage adjustment. If serum sodium correction is made quickly, neurologic sequelae may occur. Therefore, it is not recommended to advice water restriction in parallel during the initial 24 hours of drug administration, as it may have additive effect in the correction of serum sodium level. For a similar reason, close monitoring of serum sodium level is also critical when using diuretics.¹⁷⁾

If the serum sodium level rises too quickly, it can lead to osmotic demyelination syndrome, though no actual cases were reported in the SALT trial,¹²⁾ the SALTWATER study,¹⁴⁾ and the EVEREST study¹³⁾ in patients with rapid correction of serum sodium. However, several cases have been reported of osmotic demyelination syndrome, including one case in which the reason was rapid increase in serum sodium level from 122 to 167 mM/L¹⁸⁾ and, the other two cases in which 3% solution was used together.¹⁹⁾

ADVERSE EVENTS

Symptoms such as polyuria, frequent urination, thirst, dry mouth, and constipation were reported more frequently in patients receiving tolvaptan than those in in the placebo group.³⁾ Similarly, in the EVEREST study, symptoms such as thirst and nausea were reported more frequently in the tolvaptan group than that in the placebo group.¹³⁾ However, in a study involving patients with autosomal dominant polycystic kidney disease (ADPKD), the use of tolvaptan caused an increase in liver enzymes, and two of the participating patients were withdrawn due to liver injury. Consequently, the FDA recommended tolvaptan to be used for less than 30 days, especially in patients with liver disease. One study attempted to review the data of an earlier study involving patients with ADPKD to examine the characteristics of liver injury.²⁰⁾ The study revealed that hepatocyte damage in patients with ADPKD began 3 to 18 months after drug administration, and gradually improved from 1 to 4 months after discontinuation of the drug. None of these patients progressed to liver failure or chronic liver injury.²⁰⁾ This study aimed to further evaluate other long-term studies using tolvaptan in patients without ADPKD, and did not observe similar risk of liver injury in patients with HF, cirrhosis, or hyponatremia.²⁰⁾ Conclusively, the authors speculated that ADPKD patients are more susceptible to liver injury with the use of tolvaptan due to an unknown pathology.²⁰⁾ Meanwhile, in 2017, tolvaptan was tested in patients with later-stage ADPKD over a period of one year and resulted in a slower decline of the estimated glomerular filtration rate.²¹⁾ As a result, the FDA approved the use of tolvaptan in adults at risk of rapidly progressing ADPKD in 2018, to help slow the decline in kidney function. However, until now, tolvaptan has not effectively reduced overall mortality, cardiovascular mortality, or HF hospitalizations. Further studies to evaluate the safety and long-term benefits of tolvaptan should be conducted.

CONCLUSION

Tolvaptan, a vasopressin receptor antagonist, may be a milestone in the treatment of hyponatremia with the advantage of regulating free water in the body. Although tolvaptan is not associated with survival benefits and risks neurological complications and liver toxicity, tolvaptan can be considered for treatment in patients with hyponatremia and HF if it is used with caution and is closely monitored.

ARTICLE INFORMATION

Conflict of Interest

The author has no financial conflicts of interest.

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References

Citations

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