Pathophysiology of Euvolemic Hyponatremia

Patients with euvolemic hyponatremia have essentially normal extracellular volume with no signs of pitting edema or ascites. The most common cause of euvolemic hyponatremia is the syndrome of inappropriate antidiuretic hormone secretion (SIADH).¹

SIADH is the result of elevated levels of the neurohormone arginine vasopressin (AVP), which plays a critical role in regulating the body’s water-sodium balance. AVP binds to V₂ receptors in the collecting ducts of the kidneys, causing free water to be reabsorbed into the body rather than being excreted in the urine. Normally, AVP functions to maintain homeostasis; however, in SIADH, inappropriate AVP secretion results in water retention that has a dilutional effect on sodium concentration in the plasma, resulting in hyponatremia.¹

As reported in the Hyponatremia Guidelines 2007: Expert Panel Recommendations, examples of euvolemic hyponatremic conditions associated with SIADH may include:

Tumors – Tumors have been found to be ectopic sources of AVP, particularly small-cell pulmonary tumors and head and neck tumors.² Many of these tumors synthesize and secrete AVP independent of the body’s osmotic regulation system.²

Central nervous system (CNS) disorders – Many CNS disorders disrupt signaling pathways between the brain and the hypothalamus, preventing inhibition of AVP even though the patient is hypo-osmolalic.² Some CNS disorders associated with SIADH include head trauma, subarachnoid hemorrhage, tumors, infections, encephalitis, Guillain-Barré syndrome, and acute psychosis.^1,2

Induced by drugs – Certain drugs either stimulate AVP release or potentiate its effect.¹ Some of the drugs associated with SIADH include certain antipsychotic agents, antidepressants, anticonvulsants, angiotensin-converting enzyme (ACE) inhibitors, 3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”), and oxytocin.^1,2

Pulmonary diseases – Several pulmonary disorders inappropriately stimulate AVP production, leading to SIADH, including hypoxemia, hypercapnia, and pulmonary infections such as tuberculosis and pneumonia.² SIADH also occurs in patients on mechanical ventilation and in patients with chronic obstructive pulmonary disease (COPD), due to reduced pulmonary blood volume that activates baroreceptors and stimulates AVP secretion.²

REFERENCES: 1. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120:S1-S21. 2. Siragy H. Hyponatremia, fluid-electrolyte disorders, and the syndrome of inappropriate antidiuretic hormone secretion: diagnosis and treatment options. Endocr Pract. 2006;12:446-457.

View Full Prescribing Information

Indication: VAPRISOL is indicated to raise serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia.
Important Limitations: VAPRISOL has not been shown to be effective for the treatment of the signs and symptoms of heart failure and is not approved for this indication. It has not been established that raising serum sodium with VAPRISOL provides a symptomatic benefit to patients.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS
VAPRISOL is contraindicated in patients with hypovolemic hyponatremia. The coadministration of VAPRISOL with potent CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated. In addition, no benefit can be expected in patients unable to make urine.

WARNINGS & PRECAUTIONS
Hyponatremia associated with heart failure: Safety data on the use of VAPRISOL in these patients are limited. Consider other treatment options.
Overly rapid correction of serum sodium: Monitor serum sodium, volume and neurologic status and if the patient develops an undesirably rapid rate of rise of serum, VAPRISOL should be discontinued. If serum sodium concentration continues to rise, VAPRISOL should not be resumed. Serious neurologic sequelae, including osmotic demyelination syndrome, can result from over rapid correction of serum sodium. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction should be used.
Hypovolemia or Hypotension: For patients who develop hypovolemia or hypotension while receiving VAPRISOL, VAPRISOL should be discontinued, and volume status and vital signs should be monitored.
Infusion site reactions: Serious reactions have occurred. Administer through large veins and change infusion site every 24 hours.

ADVERSE REACTIONS
The most common adverse reactions (incidence ≥10%) reported in clinical trials were infusion site reactions (including phlebitis), pyrexia, hypokalemia, headache and orthostatic hypotension.

DRUG INTERACTIONS
Potent CYP3A inhibitors may increase the exposure of conivaptan and are contraindicated. Generally avoid CYP3A substrates. Exposure to coadministered digoxin may be increased and digoxin levels should be monitored.

USE IN SPECIAL POPULATIONS
Use in Patients with Hepatic Impairment
In patients with moderate to severe hepatic impairment, initiate VAPRISOL with a loading dose of 10 mg over 30 minutes followed by 10 mg/day as a continuous infusion for 2 to 4 days. If no rise in serum sodium, VAPRISOL may be titrated upward to 20 mg/day.