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The Role of V2 Receptor Antagonists in the Treatment of Hyponatremia

Under normal circumstances, there is a balance between water intake and water excretion such that plasma osmolality and the serum sodium(Na+) concentration remain relatively constant. The principal mechanism responsible for prevention of hyponatremia and hyposmolality is renal water excretion. In all hyponatremic patients, water intake exceeds renal water excretion. 
 
Excretion of water by the kidney is dependent on three factors. First, there must be adequate delivery of filtrate to the tip of the loop of Henle. Second, solute absorption in the ascending limb and the distal nephron must be preserved so that the tubular fluid will be diluted. Lastly, arginine vasopressin (AVP) levels must be low in the plasma. Of these three requirements for water excretion, the one which is most important in the genesis of hyponatremia is the failure to maximally suppress AVP levels. Given the central role of AVP in limiting renal water excretion, AVP receptor antagonists represent a physiologic and rational method to increase renal water excretion.


Introduction
Under normal circumstances, there is a balance between water intake and water excretion such that plasma osmolality and the serum sodium (Na + ) concentration remain relatively constant. The principal mechanism responsible for prevention of hyponatremia and hyposmolality is renal water excretion. In all hyponatremic patients, water intake exceeds renal water excretion.
Excretion of water by the kidney is dependent on three factors. First, there must be adequate delivery of filtrate to the tip of the loop of Henle. Second, solute absorption in the ascending limb and the distal nephron must be preserved so that the tubular fluid will be diluted. Lastly, arginine vasopressin (AVP) levels must be low in the plasma. Of these three requirements for water excretion, the one which is most important in the genesis of hyponatremia is the failure to maximally suppress AVP levels.
Given the central role of AVP in limiting renal water excretion, AVP receptor antagonists represent a physiologic and rational method to increase renal water excretion.

AVP in Regulation of Plasma Osmolality
AVP is synthesized in the supraoptic and paraventricular nucleus of the hypothalamus and then stored in the neurohypophysis. The release of AVP is exquisitely sensitive to changes in plasma osmolality. AVP is not detectable in the plasma at an osmolality below approximately 280 mOsm/kg but increases in a nearly linear fashion beginning with as little as a 2-3% increase in osmolality above this value. The extreme sensitivity of this system allows for plasma osmolality to be maintained within a narrow range.
A second major determinant of AVP release is the effective arterial blood volume. While AVP levels are very sensitive to plasma osmolality, small changes of <10% in blood pressure or blood volume have no effect on AVP levels. However, once decreases in volume or pressure exceed this value, baroreceptor-mediated signals provide persistent stimuli for AVP secretion. Baroreceptor-mediated AVP release will continue even when plasma osmolality falls below 280 mOsm/kg. Teleologically, this sys-the body behaves as if defense of blood pressure is more important than defense of osmolality, and AVP is secreted. The specific compartment whose volume is sensed in order to determine AVP secretion in this setting is the effective arterial volume. This overriding effect of volume explains the persistence of high AVP levels in hyponatremic patients with conditions such as heart failure and cirrhosis.
Other stimuli for the release of AVP include pain, nausea, and hypoxia. Inappropriate release of AVP can occur with a variety of central nervous system and pulmonary diseases as well as with drugs, particularly those that act within the central nervous system 2) . Certain tumors can synthesize and release AVP.
AVP exerts its effects on cells through three receptors.
The V 1A receptor is expressed in a variety of tissues but is primarily found on vascular smooth muscle cells.
Stimulation of this receptor results in vasoconstriction, platelet aggregation, inotropic stimulation and myocardial protein synthesis. The V 1B receptor is expressed in cells of the anterior pituitary and throughout the brain.
Stimulation of this receptor results in release of adrenocorticotropin stimulating hormone (ACTH). Stimulation of the V 1A and V 1B receptors activate phospholipase C leading to increases in inositol trisphosphate and diacylglycerol with secondary increases in cell calcium and activation of protein kinase C.
The V 2 receptor is found on the basolateral surface of the renal collecting duct and vascular endothelium where it mediates the antidiuretic effects of AVP and stimulates the release of von Willebrand factor respectively. Unlike the V 1A and V 1B receptors, binding of AVP to the V 2 receptor activates the G S -coupled adenyl cyclase system causing increased intracellular levels of cAMP. In the kidney, generation of cAMP stimulates protein kinase A which then phosphorylates preformed aquaporin-2 water channels causing trafficking and insertion of the channels into the luminal membrane of the tubular cells 3) . The insertion of the aquaporin-2 protein renders the collecting duct selectively permeable to water, which is then reabsorbed from the tubular lumen into the blood driven by the osmotic driving force of the hypertonic interstitium. In the absence of AVP, aquaporin membrane insertion and apical membrane water permeability are dramatically reduced.

Clinical Use of AVP Antagonists
Conivaptan (an intravenous V 1a-V 2 receptor antago- Conivaptan is also active as an oral formulation but its distribution has been restricted to parenteral use for short-term (4 days maximum) in-hospital administration only. This restriction is due to potent inhibitory effects of the drug on the hepatic cytochrome P 450 3A4 enzyme system and the potential for untoward drug interactions.
The inhibitory effects of other members of this class on the CYP3A4 system are more limited, allowing for oral formulations to be used in a clinical setting.
Tolvaptan is the only other AVP antagonist currently approved by the Food and Drug Administration. Unlike conivaptan, tolvaptan is an oral agent with effects confined to the V 2 receptor. The drug is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.
The efficacy of tolvaptan was evaluated in two simultaneously conducted multicenter, randomized, double blind  Another theoretical concern of blocking the V 1a receptor with conivaptan is the potential to cause further sequestration of fluid in the splanchnic vascular bed and theoretically increase the risk of hepatorenal syndrome 8) . The

AVP Antagonists in Severe Symptomatic Hyponatremia
Symptoms of hyponatremia include nausea and malaise, which can be followed by headache, lethargy, muscle cramps, restlessness, confusion and disorientation 9) . Life threatening symptoms are those of impending brain herniation and include seizures, decreased levels consciousness, and obtundation. Hypertonic saline remains the treatment of choice in those patients who are clinically determined to be severely symptomatic 10) . Vaptan therapy does result in a brisk and relatively prolonged water diuresis.
Indeed, in the first 6 hours following the parenteral administration of conivaptan there is a several mEq/L increase in the serum Na + concentration 5) . Whether this time course of correction is sufficient to abort fatal hyponatremic encephalopathy is simply not known. Such patients to date have been excluded from clinical studies since randomization in a placebo controlled trial would be clearly unethical in such subjects, and not using hypertonic saline might also be considered unsafe.
Although not well studied, one could co-administer conivaptan along with hypertonic saline and anticipate a more rapid initial rise in the serum Na + . Once stabilized, the hypertonic saline could be discontinued and the remainder of correction be accomplished by use of the receptor antagonist alone. This strategy would help to minimize the likelihood of volume overload due to the use of hypertonic saline but would require frequent monitoring of the serum Na + to ensure the rate of correction was within accepted guidelines.

AVP Antagonists in Patients with Mild to Moderate Symptoms of Hyponatremia
Hospitalized patients with mild to moderate symptoms of hyponatremia can be considered ideal candidates for the use of V 2 receptor antagonists. Both conivaptan and tolvaptan can be expected to increase the serum Na + concentration to a greater extent and more predictably than fluid restriction alone. The superiority of these drugs would be particularly evident in those who require ongoing fluid administration for any number of reasons such as parenteral administration of antibiotics or proton pump inhibitors 11) .  12) . For this The decision to use a vaptan on a more prolonged basis is made on a case by case basis. When the underlying .

AVP Antagonists in Asymptomatic Hyponatremic Patients
One remaining question concerning the use of vaptan therapy is whether they are helpful in hyponatremic pa- Second, asymptomatic hyponatremic patients exhibit subtle disturbances in gait that improve following correction of the serum Na + concentration 14,15) . In this regard, case control studies have shown an association between hyponatremia and risk of falls and fractures particularly in the elderly population 16,17) . Chronic hyponatremia has been shown to cause a reduction in bone mass in an experimental model of SIADH and hyponatremia is associated with osteoporosis in cross-sectional human data 18) .
Fall-related injury is associated with substantial adverse psychological and physical outcomes and is a cause of both death and disability in this population. It would be of considerable socioeconomic benefit if treatment of asymptomatic hyponatremia were able to reduce the risk of this complication.
Lastly, hyponatremia is associated with increased morbidity and mortality but generally the low Na + concentration is merely thought to be marker of the severity of the underlying disease and not a direct contributor to the adverse outcome 19,20) . For example in decompensated heart failure there is an inverse relationship between the degree of hyponatremia and the extent of neurohormonal activation. Adverse effects resulting from persistent activation of the renin-angiotensin-aldosterone system and sym- pathetic nerve activity are thought to be the mechanism underlying the increase in mortality in hyponatremic patients with heart failure. Nevertheless, it has been suggested that hyponatremia itself, the associated hypotonicity, and/or elevated levels of AVP might exert adverse effects on the cardiovascular system or other organ systems and therefore play a contributory role in patient morbidity and mortality. While it remains speculative as to whether correction of the hyponatremia per se will improve patient outcomes, the V 2 receptor antagonists offer an opportunity to test this uncertainty in patients with euvolemic and hypervolemic hyponatremia.