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HYPONATREMIA AND THE EMERGING ROLE OF TOLVAPTAN IN CARDIOLOGY. DR SHREETAL RAJAN NAIR. Hyponatremia. Hyponatremia , defined as a serum sodium <135 mEq /L, is the most common electrolyte disorder encountered in hospitalized patients.
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HYPONATREMIA AND THE EMERGING ROLE OF TOLVAPTAN IN CARDIOLOGY DR SHREETAL RAJAN NAIR
Hyponatremia Hyponatremia, defined as a serum sodium <135 mEq/L, is the most common electrolyte disorder encountered in hospitalized patients. Is a significant independent predictor of medical prognosis and costs.
Prevalence of hyponatremia Prevalence of hyponatremia ([Na+] <135 mEq/L): 28% in hospitalized patients 21% in hospital clinics and 7% in outpatient community care clinics ClinChimActa. 2003;337(1-2):169-72.
Prevalence of hyponatremia in hospitalized patients with heart failure or cirrhosis Gheorghiade M, Rossi JS, Cotts W et al. Arch Intern Med. 2007;167(18):1998-2005, AngeliP, Wong F, Watson H, Gines P. Hepatology. 2006;44(6):1535-1542.
Classification of hyponatremia Hypervolemichyponatremia, Euvolemichyponatremia, Hypovolemichyponatremia
Hypervolemichyponatremia • Dilutional form of hyponatremia, occurs when there is an increase in total body water but a relatively smaller increase in the total serum sodium. • 3 primary causes of hypervolemichyponatremia: • HF, • Cirrhosis of the liver, and • Renal disease. • Clinical signs • evidence of volume expansion, such as the presence of clinically evident edema, ascites, and pulmonary edema
Euvolemichyponatremia • It occurs when there is an increase in total body water without a corresponding increase in total serum sodium, though the increase in body water is not sufficient to promote clinically evident edema. • Causes: • Syndrome of inappropriate antidiuretic hormone (SIADH) • Patients with euvolemichyponatremia have no signs of volume depletion or volume expansion.
Hypovolemichyponatremia Depletional form of hyponatremia, occurs when there is a decrease in both total body water and total serum sodium, with a disproportionately greater decrease in serum sodium. Hypovolemic hyponatremia is usually due to an excess of fluid loss. It is commonly caused by fluid loss through vomiting or diarrhea or is due to the use of diuretic therapy. Clinical signs of volume depletion include orthostatic decreases in blood pressure, increases in pulse rate, dry mucus membranes, and decreased skin turgor
Signs, symptoms, and consequences of hyponatremia Serum [Na+] 130-135 mEq/L Serum [Na+] 120-130 mEq/L Serum [Na+] <120 mEq/L • Malaise • Unsteadiness • Headache • Nausea • Vomiting • Fatigue • Confusion • Muscle cramps •Asymptomatic • Headache • Nausea • Vomiting • Fatigue • Confusion • Muscle cramps • Depressed reflexes • Headache • Restlessness • Lethargy • Seizures • Brain-stem herniation • Respiratory arrest • Death .
Vasopressin Is a nine-amino-acid peptide synthesized in the neurosecretory cells of the supraopticand paraventricularnuclei of the hypothalamus and is stored in the posterior pituitary gland. Upon its release, vasopressin binds to and activates V2-receptors in the renal collecting duct, leading to the insertion of water channels into the wall of the collecting duct by a cAMP-dependent mechanism. This series of events stimulates water reabsorption. Thus, increased vasopressin promotes an increase in electrolyte-free water reabsorption and more concentrated urine as water passively diffuses out of the renal tubule. Circulating vasopressin can also cause vasoconstriction by activating V1a-receptors on smooth muscle cells in blood vessels. V1b-receptors are found on corticotropes, and they contribute to increased ACTH secretion.
Vasopressin • The primary role of vasopressin is • to control total body water, electrolyte balance, and blood pressure by regulating vascular tone and water excretion by the kidney. • Increased vasopressin levels due to nonosmotichemodynamic stimuli is the mechanism responsible for water retention and hyponatremia in edema-forming disorders such as HF and cirrhosis.
Heart failure: • HF patients may have increased vasopressin secretion • in response to decreases in arterial blood pressure and circulating blood volume. • Decrease in blood volume or blood pressure of approximately 8% to 10% - stimulates vasopressin secretion. • The underloading of arterial baroreceptors is responsible for the stimulation of vasopressin secretion. • Vasopressin increases the passive reabsorption of electrolyte-free water in the kidney in an attempt to restore perfusion pressure- may result in hypervolemichyponatremia.
Factors stimulating the release of vasopressin • The 2 key mechanisms regulating fluid/electrolyte balance are • Renal water reabsorption, due to vasopressin, and • Drinking behavior driven by thirst perception. • Vasopressin increases passive water reabsorption in the kidney and results in more concentrated urine, which is reflected by increased urine osmolality. • Hyponatremiamay result from sodium loss, excessive fluid intake, or, more frequently, water retention.
Factors stimulating the release of vasopressin Vasopressin release due to nonosmotic stimuli is responsible for the predominance of euvolemic and hypervolemichyponatremia (e.g., SIADH, HF, or Cirrhosis). Osmotic stimuli Nonosmotic stimuli of vasopressin release: These stimuli include decreased effective arterial blood volume or blood pressure, pain, nausea, stress, and a variety of drugs. Decreases of approximately 8% to 10% in arterial blood pressure and circulating blood volume may activate baroreceptors in the carotid sinus, aortic arch, cardiac atria, and pulmonary venous system, which stimulate the release of vasopressin.
Hyponatremia - HF . OPTIMIZE-HF registry, Eur Heart J, 2007;28(8):980–88. The Organized Program to Initiate Life Saving Treatment in Patients Hospitalized for Heart Failure (OPTIMIZE-HF) registry recorded that 25.3% of 47,647 heart failure patients had hyponatremia on admission. In this registry, patients with hyponatremia had increased in-hospital and postdischarge mortality and longer median hospital stay compared with those with higher sodium levels.
Hyponatremia Is Associated with Higher Mortality Lancet. 1982;2(8289):101-2. Clin Sci. 1939;4:73-7. Br Med J. 1983;286(6366):671-3. Br Med J. 1979;1(6173):1242-6.
Hyponatremia - HF Currently, there are no guidelines for the appropriate way to deal with low serum sodium levels in heart failure patients; Treatment generally consists of fluid restriction, which has not been clinically examined in this setting. Vasopressin receptor antagonists that selectively increase solute-free water excretion by the kidneys are showing evidence of being effective for the treatment of hyponatremia in heart failure.
Rationale of present therapies • Increase the amount of sodium in the body • Decrease intake of water • Prevent water reabsorption into the body and prevent dilution
Current therapies of hyponatremia Isotonic and hypertonic saline for short-term use, and fluid restriction, demeclocycline, salt tablets, and rarely mineralocorticoids and urea for long-term use. All of these therapies work in specific circumstances, but none are ideal and all have limitations for a variety of different reasons, including variable efficacy, slow responses, intolerable side effects such as thirst, and dangerous toxicities such as ODS.
Current therapies of hyponatremia Fluid restriction • Is that fluid restriction usually cannot be sustained • Because it produces intolerable dehydration and thirst. • Secondly, fluid restriction works very slowly—generally 1 to 2 mEq/L per day even under a severe fluid restriction of <500 mL/d. • Consequently, this method can take many days to correct a low serum [Na+]. Am J Med. 1957;23(4):529-42.
Current therapies of hyponatremia All treatments other than demeclocycline and the vaptans fail to attack the mechanistic cause of dilutionalhyponatremia, which is inappropriately elevated plasma AVP levels.
Aquaretic therapies • The newest addition in hyponatremia treatment
rationale for aquaretic therapies The appropriate method of treating hyponatremia in HF is by removing excess total body water That is the objective of fluid restriction that decreases body water via insensible losses of water, but very inefficiently and very slowly. A better therapy would be blocking the process of urinary concentration, which originates from AVP binding to the V2 receptor in the kidney and would prevent all the downstream intracellular consequences of V2 receptor activation including the insertion of the aquaporin water channels into the apical membrane of the collecting duct cells.
Was approved by US FDA in february 19,2009 • Tolvaptan (INN), also known as OPC-41061, is a 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 (SIADH).
Tolvaptan Mechanism of action of the Tolvaptan: stimulate increased water excretion from the kidney. Importantly, blocking the V2 receptor has no effect on sodium or potassium excretion; it simply causes increased excretion of water without increased solute. Therefore, vaptans are electrolyte-sparing, and it is more appropriate to call their effect “aquaresis” or increased urinary water excretion rather than diuresis, which classically has been defined as increased urinary water and solute (particularly sodium and potassium) excretion.
Mechanism of action When taken orally, 15- to 60-mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium. Am J Med. 2007;120(suppl 11A):S1-S21 Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the human V2-receptor 1.8 times that of native vasopressin. Tolvaptan affinity for the V2-receptors is approximately 29 times that for the V1a-receptor. Urinary excretion of sodium and potassium, and plasma potassium concentrations are not significantly changed.
Targeted MOA: Vasopressin V2-receptor antagonism Tolvaptan N Engl J Med. 2005;352(18):1847-1850
Targeted MOA:Vasopressin V2-receptor antagonism • The resulting increase in urine output produced by a V2-receptor antagonist is quantitatively similar to diuretics such as loop diuretics, but qualitatively different in that electrolyte-free water is excreted without a significant increase in urine solute excretion, including sodium and potassium. • For this reason, the renal effects produced by V2-receptor antagonists are termed aquaresis, to distinguish them from the renal effects produced by some diuretic agents, which include not only increased water excretion but also natriuresis and kaliuresis Binding of a V2-receptor antagonist, such as tolvaptan, blocks the activation of the receptor by endogenous vasopressin.
Dosing and titration The usual starting dose for (tolvaptan) is 15 mg administered once daily without regard to meals. The dose of Tolvaptan may be increased to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium. During initiation and titration, frequently monitor for changes in serum electrolytes and volume to prevent overcorrection of serum sodium
Tolvaptan is contraindicated in the following conditions: • Urgent need to raise serum sodium acutely • Inability of the patient to sense or appropriately respond to thirst • Hypovolemichyponatremia • Concomitant use of strong CYP 3A inhibitors • Anuric patients
Adverse effects • Problems with speech or muscle control, trouble swallowing, trouble moving your arms and legs, mood changes, and seizure (convulsions) – may be osmotic demyelination syndrome due to rapid correction of sodium • weakness or fainting; • melaena; • Hemoptysis,hemetemesis; Less serious side effects may include: • dry mouth; • increased thirst • abnormal frequent urination (pollakiuria) • constipation; or • loss of appetite, fruity breath odor, drowsiness, dry skin, nausea, vomiting.
SALT 1 & 2 Study of Ascending Levels of Tolvaptan in Hyponatremia
SALT-1 and SALT-2 N Engl J Med 2006;355:2099-112. • Multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptanwas evaluated in patients with euvolemic and hypervolemichyponatremia. • N= 448 patients • Hypervolemic or euvolemichyponatremia resulting from (HF, cirrhosis, or SIADH) • Oral placebo (n=223) or • Oral Tolvaptan(n=225) in a titrated regimen of 15 to 60 mg once daily.
