Vasopressin receptor antagonist

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A vasopressin receptor antagonist (VRA) is an agent that interferes with action at the vasopressin receptors. Most commonly VRAs are used in the treatment of hyponatremia, especially in patients with congestive heart failure, liver cirrhosis or SIADH. [1]




The "vaptan" drugs act by directly blocking the action of vasopressin at its receptors (V1A, V1B and V2). These receptors have a variety of functions, with the V1A and V2 receptors are expressed peripherally and involved in the modulation of blood pressure and kidney function respectively, while the V1A and V1B receptors are expressed in the central nervous system. V1A is expressed in many regions of the brain, and has been linked to a variety of social behaviors in humans and animals.

The vaptan class of drugs contains a number of compounds with varying selectivity, several of which are either already in clinical use or in clinical trials as of 2009. [2] [3] [4]

Unselective (mixed V1A/V2)
V1A selective (V1RA)
V1B selective (V3RA)
V2 selective (V2RA)

Demeclocycline and lithium

Demeclocycline, a tetracycline antibiotic, is sometimes used to block the action of vasopressin in the kidney in hyponatremia due to inappropriately high secretion of vasopressin (SIADH), when fluid restriction has failed. [5] Demeclocycline is not a direct antagonist of the vasopressin receptors however, but rather inhibits activation of the intracellular second messenger cascade of this receptor in the kidney by an unknown mechanism. [6] [7]

Lithium, as lithium carbonate, possesses similar properties to those of demeclocycline on the action of vasopressin in the kidney, and was used clinically before demeclocycline, which largely superseded it for this indication. [6] [7]

Medical use


V2R antagonists have become a mainstay of treatment for euvolemic (i.e., SIADH, postoperative hyponatremia) and hypervolemic hyponatremia (i.e., CHF and cirrhosis). [8] V2RAs predictably cause aquaresis leading to increased [Na+] in majority of patients with hyponatremia due to SIADH, CHF, and cirrhosis. The optimum use of VRAs has not yet been determined, but some predictions can be made with reasonable certainty. For hyponatremia in hospitalized patients, who are unable to take medication orally or for those in whom a more rapid correction of hyponatremia is desired, conivaptan (V1/V2R antagonist) will likely be the preferred agent. Selective V2R antagonists such as tolvaptan, lixivaptan etc. will likely be useful in patients for whom oral therapy is suitable and for more chronic forms of hyponatremia. [8]

Congestive heart failure

Neurohormonal activation characteristic of CHF, including increased renin, angiotensin, aldosterone, and catecholamines, contributes to progression of CHF. It has been suggested that cardiovascular mortality may be reduced by selective V2RA such as tolvaptan in the higher risk group with kidney function impairment or severe congestive findings. [8] But until FDA indication is granted for use in CHF with or without accompanying hyponatremia, VRAs are not recommended in patients with CHF. [8]


V2RA may be particularly beneficial in the treatment of patients with advanced liver cirrhosis and ascites. [9] Blockade of V2R will induce an effective aquaresis and inhibition of V2-mediated vasodilation. This aquaresis, in combination with a diuresis, may provide a potential therapy for patients with resistant ascites. V2 receptor antagonism increases plasma vasopressin concentration, which may cause unopposed hyperstimulation of the vasoconstrictor V1 receptor. Given the potential hyperstimulation of V1R, V2RA may have additional secondary preventative benefits in patients with cirrhosis through a reduction in portal pressure and a decreased risk of variceal bleeding. [9]

Polycystic kidney disease

Polycystin defects increase intracellular cAMP, secondary messenger for vasopressin acting at V2R, leading to cyst development. [8] cAMP-dependent genes promote fluid secretion into developing renal cysts and increase cell proliferation. Studies in several animal models of polycystic kidney disease have shown a reduction in kidney size and cyst volume after treatment with specific V2 receptor antagonist. [8] Full scale therapeutic trials of V2RAs in patients with autosomal dominant polycystic kidney disease are currently ongoing. [8]

Nephrogenic diabetes insipidus

Congenital nephrogenic diabetes insipidus (NDI) may result from V2R or aquaporin-2 (AQP2) mutations. Exogenously administered V2R antagonists can bind to misfolded intracellular V2R, and improve transport of V2R to the cell membrane. [8] Clinical studies in patients with X-linked NDI showed that the selective V1R antagonist relcovaptan (SR49059, Sanofi-Aventis) significantly increased urine osmolality and decreased 24-hour urine flow. [8] Thus V1R and/or V2R antagonists may serve as molecular chaperones to mitigate misfolding defects in selected patients with type 2 NDI. [8]

Related Research Articles

Autosomal dominant polycystic kidney disease human disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent, potentially lethal, monogenic human disorder. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. It is also the most common of the inherited cystic kidney diseases — a group of disorders with related but distinct pathogenesis, characterized by the development of renal cysts and various extrarenal manifestations, which in case of ADPKD include cysts in other organs, such as the liver, seminal vesicles, pancreas, and arachnoid membrane, as well as other abnormalities, such as intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse, and abdominal wall hernias. Over 50% of patients with ADPKD eventually develop end stage kidney disease and require dialysis or kidney transplantation. ADPKD is estimated to affect at least one in every 1000 individuals worldwide, making this disease the most common inherited kidney disorder with a diagnosed prevalence of 1:2000 and incidence of 1:3000-1:8000 in a global scale.

Hyponatremia is a low sodium concentration in the blood. It is generally defined as a sodium concentration of less than 135 mmol/L, with severe hyponatremia being below 120 mEq/L. Symptoms can be absent, mild or severe. Mild symptoms include a decreased ability to think, headaches, nausea, and poor balance. Severe symptoms include confusion, seizures, and coma.

Vasopressin mammalian protein found in Homo sapiens

Vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon of that cell, which terminates in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure.

Angiotensin II receptor blocker group of pharmaceuticals that modulate the renin–angiotensin system

Angiotensin II receptor blockers (ARBs), formally angiotensin II type 1 (AT1) receptor antagonists, also known as angiotensin receptor blocker, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II type 1 receptor (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by excessive unsuppressible release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. Unsuppressed ADH causes an unrelenting increase in solute-free water being returned by the tubules of the kidney to the venous circulation.

Conivaptan chemical compound

Conivaptan is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia. The compound was discovered by Astellas and marked in 2006. The drug is now marketed by Cumberland Pharmaceuticals, Inc.

Demeclocycline chemical compound

Demeclocycline, also known under the brand names Detravis, Meciclin, Mexocine, Clortetrin, is a tetracycline antibiotic which was derived from a mutant strain of Streptomyces aureofaciens.

Nephrogenic diabetes insipidus (NDI) is a form of diabetes insipidus primarily due to pathology of the kidney. This is in contrast to central or neurogenic diabetes insipidus, which is caused by insufficient levels of antidiuretic hormone. Nephrogenic diabetes insipidus is caused by an improper response of the kidney to ADH, leading to a decrease in the ability of the kidney to concentrate the urine by removing free water.

Primary polydipsia dry mouth and excessive fluid consumption in the absence of physiological stimuli to drink

Primary polydipsia, or psychogenic polydipsia, is a form of polydipsia characterised by excessive fluid intake in the absence of physiological stimuli to drink. Psychogenic polydipsia which is caused by psychiatric disorders, often schizophrenia, is often accompanied by the sensation of dry mouth. Some forms of polydipsia are explicitly non-psychogenic. Primary polydipsia is a diagnosis of exclusion.

Vasopressin receptor 2 protein-coding gene in the species Homo sapiens

Vasopressin receptor 2 (V2R), or arginine vasopressin receptor 2, is a protein that acts as receptor for vasopressin. AVPR2 belongs to the subfamily of G-protein-coupled receptors. Its activity is mediated by the Gs type of G proteins, which stimulate adenylate cyclase.

The actions of vasopressin are mediated by stimulation of tissue-specific G protein-coupled receptors (GPCRs) called vasopressin receptors that are classified into the V1 (V1A), V2, and V3 (V1B) receptor subtypes. These three subtypes differ in localization, function and signal transduction mechanisms.

Tolvaptan selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone

Tolvaptan (trade names Samsca, Jinarc, and others) is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.

An aquaretic is a novel class of drug that is used to promote aquaresis, the excretion of water without electrolyte loss. Strictly speaking, aquaretics are not diuretics, but are sometimes classified as such.

Satavaptan chemical compound

Satavaptan is a vasopressin-2 receptor antagonist which was investigation by Sanofi-Aventis and was under development for the treatment of hyponatremia. It was also being studied for the treatment of ascites. Development was discontinued in 2009.

Lixivaptan chemical compound

Lixivaptan (VPA-985) is a phase III pharmaceutical being developed by Cardiokine, Inc., a specialty pharmaceutical company based in Philadelphia, PA, focused on the development of pharmaceuticals for the treatment and prevention of cardiovascular diseases. Lixivaptan is, as of May 2010, in Phase III clinical trials involving patients with hyponatremia, including those with concomitant heart failure. Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. Lixivaptan may help some patients eliminate excess fluids while retaining electrolytes.

Hypoosmolar hyponatremia is a condition where hyponatremia associated with a low plasma osmolality. The term "hypotonic hyponatremia" is also sometimes used.

Management of heart failure requires a multimodal approach. It involves a combination of lifestyle modifications, medications, and possibly the use of devices or surgery.

Indantadol chemical compound

Indantadol is a drug which was formerly being investigated as an anticonvulsant and neuroprotective and is now under development for the treatment of neuropathic pain and chronic cough in Europe by Vernalis and Chiesi. It acts as a competitive, reversible, and non-selective monoamine oxidase inhibitor, and as a low affinity, non-competitive NMDA receptor antagonist. A pilot study of indantadol for chronic cough was initiated in October 2009 and in April 2010 it failed to achieve significant efficacy in neuropathic pain in phase IIb clinical trials.

A fluid restriction diet is a diet which limits the amount of daily fluid consumption. Besides beverages, many foods also include fluids which needs to be taken into consideration. A fluid restrictive diet assists in preventing the build up of fluids in the body. Reducing fluid intake can alleviate stress on the body and may reduce additional complications. A fluid restriction diet is generally medically advised for patients with "heart problems, renal disease, liver damage including cirrhosis, endocrine and adrenal gland issues, elevated stress hormones and hyponatremia. Patients with heart failure are recommended to restrict fluid intake down to 2 quarts per day.

Diuretic Substance that promotes the production of urine

A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way. Alternatively, an antidiuretic, such as vasopressin, is an agent or drug which reduces the excretion of water in urine.


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