A Comprehensive Review of Vaptans in the Treatment of Hyponatremia

This report provides a detailed review of vaptans, a class of vasopressin receptor antagonists (VRAs), and their application in treating hyponatremia, a condition characterized by low blood sodium levels. It explores the mechanisms of action, focusing on aquaresis, and highlights the potential applications of vaptans like tolvaptan and conivaptan in managing euvolemic and hypervolemic hyponatremia. The report reviews clinical trials that demonstrate the efficacy of vaptans in improving serum sodium levels, particularly in cirrhotic patients, and their potential use in conditions like SIADH associated with lung cancer. However, the report also outlines the limitations of vaptans, including contraindications, ineffectiveness in certain hyponatremic conditions, and the need for more cost-effectiveness data. Despite these limitations, the report acknowledges the benefits of vaptans, such as their role in correcting postoperative hyponatremia and maintaining electrolyte balance. The conclusion emphasizes the need for further research to understand the long-term effects and efficacy of VRAs, while recognizing their current benefits in managing hyponatremia.

Running Head: VAPTANS IN HYPONATREMIA: USE AND LIMITATIONS
VAPTANS IN HYPONATREMIA: USE AND LIMITATIONS
Name of the student
Name of the University
Author Note

1
VAPTANS IN HYPONATREMIA: USE AND LIMITATIONS
Table of Contents
Introduction................................................................................................................................2
Review........................................................................................................................................2
Potential applications and uses of Vaptans............................................................................2
Limitation of vaptans.............................................................................................................4
Summary....................................................................................................................................4
Conclusion..................................................................................................................................5
References..................................................................................................................................6

2
VAPTANS IN HYPONATREMIA: USE AND LIMITATIONS
Introduction
Hyponatremia is a condition of electrolyte abnormality characterized by decreased
blood sodium concentration (<136 mEq/L), possibly caused by excess water retention in the
body. It is the most common form of electrolyte disorder encountered clinically and
contributes towards clinical, societal, and economic burdens (1). Traditional clinical
management of hyponatremia presents some drawbacks, for which newer treatment efficacies
are being explored. In this context, vasopressin receptor antagonists (VRA) are utilized in
pharmaceutical therapy of hyponatremia. Vaptans are a class of nonpeptide V2 receptor
antagonists used to treat euvolemic and hypervolemic hyponatremia by the process of
aquaresis (2). This paper aims to outline the potential applications and limitations of vaptans
in the treatment of hyponatremia.
Review
Potential applications and uses of Vaptans
Vaptans, also known as aquaretics, act by inhibiting the binding of the vasopressin
receptors to the V2 receptors on the renal collecting duct cells. As a result of the receptor
inactivation, reabsorption of free water is prevented, and urine volume is increased. Thus
aquaresis takes place where solute-free urine is excreted to counteract the antidiuresis
mediated by V2 receptors (3). Vaptans are orally and intravenously active pharmaceuticals
that can be administered to significantly correct chronic hypotonic forms of hyponatremia.
Tolvaptan and Conivaptan are the two most investigated vaptans that have been researched
upon for their clinical implications and benefits in treating hyponatremia. Other categories
include mozavaptan, lixivaptan, RWJ351647, and satavaptan. Binding to the V2 receptors for
these molecules occur with a relative specificity, except for conivaptan, which exhibits
affinity for two receptors, V1a and V2 simultaneously (4).

3
VAPTANS IN HYPONATREMIA: USE AND LIMITATIONS
The efficacy of vaptans in euvolemic hyponatremia has been particularly emphasized
through multiple clinical studies. Several clinical trials have been conducted with vaptan
treatment ever since the inception of this novel therapeutic. Patients with euvolemic and
hypervolemic hyponatremia were included in the studies to evaluate the impact of vaptans in
reducing the negative burden of hyponatremia in these patients. For the individuals who
received conivaptan treatment, a prolonged and rapid rise in their baseline serum sodium
(Na+) level was observed (5).
Studies indicate that tolvaptan treatment remarkably improves the serum sodium
concentrations and survival rates in cirrhotic patients experiencing hyponatremia. With
tolvaptan treatment, their serum sodium levels returned within the normal range. The safety
profile and efficiency of the use of Tolvaptan were analyzed through a controlled meta-
analysis study in hyponatremic patients, where it increased the serum sodium concentrations,
improved the 24-hour urine output and total fluid balance of the patients. Such results suggest
the effectiveness of Tolvaptan in enhancing short-range survival in highly compromised
cirrhotic hyponatremia patients with restored serum sodium, and increasing the urine volume
and maintaining the fluid homeostasis (6).
Hyponatremia is prevalent in patients of lung cancer, where a syndrome of
inappropriate release of antidiuretic hormone (SIADH) acts as the underlying cause. Those
patients who need immediate chemotherapy for their ongoing malignancy may have the
potential to get the benefit of tolvaptan-treatment, according to evidence based clinical
studies. This is because they require adequate hydration along with chemotherapy, where the
use of tolvaptan may provide relief (7).

4
VAPTANS IN HYPONATREMIA: USE AND LIMITATIONS
Limitation of vaptans
Although there is evidence of the possible benefits of vaptans from many clinical
studies suggesting their success in reducing the mortality and morbidity rates caused by
hyponatremia, there are some cases in which the applications of vaptans are restricted.
Treatment of vaptans involves various contraindications in hypovolemia, severe
hyponatremia (Na+ < 120 mmol/L), patients with a history of VRA hypersensitivity, adipsia,
anuria and in cases of concomitant use of drugs like CYP3A4 inhibitors that increase plasma
Na+ levels. Few forms of hyponatremia cannot be resolved with vaptan treatment. They are
ineffective in vasopressin independent hyponatremia where the fluid imbalance is not
mediated by vasopressin hormone and in the nephrogenic syndrome of inappropriate
antidiuresis (NSIAD). Similarly, vaptans have a minimal efficacy in low GFR induced
hyponatremia and in hyponatremia caused by transient high vasopressin states like deficiency
of cortisol or drug-induced SIADH. Despite their relative safety and effectiveness,
considerable uncertainties associated with the vaptan use in hyponatremia still exist. A
primary underlying concern is the scarcity of data showing cost-effectiveness. The high cost
of these drugs cannot be justified without sufficient evidence of clinically significant
outcomes. There is a lack of clinical research displaying proven benefits in equivocally
diminishing the mortality and morbidity rates attributed to hyponatremia (8).
Summary
Vaptans show significant results in treating euvolemic and hypervolemic
hyponatremia by the mechanism of aquaresis. By successfully inhibiting the action of
arginine-vasopressin in binding to the renal collecting duct cells, they can effectively reduce
the abnormal fluid balance and subsequently increase or correct the reduced levels of serum
sodium. The multiple clinical applications of vaptans, specifically tolvaptan, which is orally
ingestible and conivaptan, which is administered intravenously, are in the treatment of

5
VAPTANS IN HYPONATREMIA: USE AND LIMITATIONS
chronic hypotonic hypernatremia. Various research studies indicate the short term efficacy of
tolvaptan a conivaptan in restoring low sodium levels, increasing volume of urine as well as
maintain or resolve water imbalance. Despite this evidence, there is a current limitation of
vaptan treatment in some forms of hyponatremia and disease-specific conditions. Vaptans are
deemed ineffective in cases of vasopressin-independent hyponatremia and NSAID and
exhibit no to low efficacy in hyponatremia caused as a result of low GFR rate or increased
vasopressin states like deficiency of cortisol and drug-induced SIADH. Such drawbacks
reduce the applicability of vaptans in a wide range of hyponatremic conditions. However,
despite the pitfalls in vaptan use, there are some unprecedented benefits of this class of
pharmaceuticals. Intravenous conivaptan has the potential to be utilized, particularly in the
correction of postoperative hyponatremia, which is a vulnerable state of the body to undergo
several electrolyte imbalances.
Conclusion
It can be deduced from evaluating the potential roles and limitations of vaptans in
hypernatremia treatment, that there is a significant gap in scientific research regarding long
term consequences and efficacy of VRAs. Even though there is proof that vaptans
successfully address the concerns in euvolemic and hypervolemic hyponatremia, it cannot be
administered in all cases. For hyponatremia induced by drugs, low GFR rate, and high
transient vasopressin states, vaptans demonstrate no ppotential effects. However, the capacity
of vaptans in the correction of postoperative hyponatremia, maintaining electrolyte balance,
and restoring abnormal serum sodium levels in the body, along with effective aquaresis,
proves to be beneficial.

6
VAPTANS IN HYPONATREMIA: USE AND LIMITATIONS
References
1. Hoorn EJ, Zietse R. Diagnosis and treatment of hyponatremia: compilation of the
guidelines. Journal of the American Society of Nephrology. 2017 May 1;28(5):1340-
9.
2. Filippatos T, Elisaf M, Liamis G. Pharmacological management of hyponatremia.
Expert opinion on pharmacotherapy. 2018 Aug 13;19(12):1337-44.
3. Ramesh G. Hyponatremia: A role for vasopressin receptor antagonists?. Journal of
anaesthesiology, clinical pharmacology. 2018 Apr;34(2):198.
4. Naafs MA. The Vasopressin V2 Receptor Antagonists: The Vaptans.
5. Li B, Fang D, Qian C, Feng H, Wang Y. The efficacy and safety of tolvaptan in
patients with hyponatremia: a meta-analysis of randomized controlled trials. Clinical
drug investigation. 2017 Apr 1;37(4):327-42.
6. Wang S, Zhang X, Han T, Xie W, Li Y, Ma H, Liebe R, Weng H, Ding HG.
Tolvaptan treatment improves survival of cirrhotic patients with ascites and
hyponatremia. BMC gastroenterology. 2018 Dec 1;18(1):137.
7. Thajudeen B, Salahudeen AK. Role of tolvaptan in the management of hyponatremia
in patients with lung and other cancers: current data and future perspectives. Cancer
management and research. 2016;8:105.
8. Rondon-Berrios H, Berl T. Vasopressin receptor antagonists in hyponatremia: uses
and misuses. Frontiers in medicine. 2017 Aug 21;4:141.