In this review, the pathophysiology of hyponatremia is discussed along with its standard treatment and the use of new vasopressin antagonists, conivaptan and tolvaptan.
Homeostasis of electrolytes and fluid is necessary for normal physiologic functioning. The most commonly encountered electrolyte abnormality is hyponatremia.1 Hyponatremia (low sodium) is defined as a serum sodium (Na+) <135 mEq/L, and may be associated with increased mortality especially in the Intensive Care Unit (ICU).2 Mortality increases in a linear fashion as serum Na+ decreases. In patients with Na+ <120 mEq/L, mortality rates have been described to be as high as 60%.3 These rates may be due to underlying medical conditions that predispose the patient to low Na+, and not the actual hyponatremia itself. Hyponatremia has been documented to occur in 30% to 42.6% of hospitalized patients.4 Specifically, a retrospective study of 98 patients found the incidence of hyponatremia to be 24.5% in ICU patients.5
Na+ homeostasis is primarily regulated by the kidneys. Na+ absorbed from exogenous sources is excreted by glomerular filtration with a portion reabsorbed from the proximal tubules. Aldosterone regulates Na+ reabsorption by activating the Na+ ion channel in the distal tubule epithelial cells of the kidney.6 Once synthesized and released from the adrenal cortex, aldosterone plays a crucial role in the renin-angiotensin-aldosterone system to maintain blood pressure by causing Na+ and water retention. Arginine vasopressin (AVP), formerly called antidiuretic hormone, indirectly regulates Na+ by water and osmolality regulation. AVP activity increases the aquaporin channels to enhance water reabsorption, in essence diluting the Na+ and overall decreasing the osmolality. When the atrial natriuretic peptide is released from the atrium due to stretch during increased central venous pressure, it antagonizes aldosterone to inhibit the renin-angiotensin-aldosterone system and AVP pathways. When B-type natriuretic peptide is released from the ventricles due to stretch related to heart failure, it also antagonizes aldosterone. Other factors such as dopamine sympathetic nerve activity and various renal prostaglandins may also influence Na+ balance.7
Since hyponatremia is a syndrome of distorted tonicity, it is important to also discuss water balance. Na+ and negative anions (chloride and bicarbonate) comprise more than 90% of the osmolality of the extracellular fluid due to the inability to move freely across the cell membrane, and thereby induce a transcellular shift of water. The Na+-K+-ATPase pump maintains the differential concentrations between the intra- and extracellular fluid. Serum Na+ may change by up to 3% as a natural variation, so the kidneys must maintain an osmolality of 275 to 290 mOsm/kg despite water intake.8 Water balance is regulated by exogenous intake and AVP. AVP is synthesized in the hypothalamus, then stored and secreted by the posterior pituitary gland. Once stimulated by osmoreceptors due to a change in osmolality of 1% to 2% or hypovolemia, AVP released will bind to vasopressin-2 (V2) receptors on the basolateral surface of the renal tubules. Through second messengers reactions, aquaporins are inserted into the apical tubular lumen surface to promote water reabsorption in the collecting duct of the kidneys.5 AVP also stimulates thirst. Too much AVP, otherwise known as the Syndrome of Inappropriate Antidiuretic Hormone (SIADH), disproportionately allows water reabsorption, resulting in hyponatremia.
STANDARD TREATMENTS OF HYPONATREMIA
The treatment goals for hyponatremia are to correct the underlying cause and the serum Na+. Intravenous sodium chloride (NaCl) solution and 1-g salt tablets of NaCl are used to replace Na+. For hypervolemic and euvolemic hyponatremia, diuretics should be held if possible (except in patients with fluid overload due to chronic heart failure), and fluids should be restricted to <800 mL/d.9,10 The rate of correction for acute hyponatremia developing within 24 to 48 hours is <12 mEq/L/d, in contrast to chronic hyponatremia that should <8 mEq/L/d. There is no data to suggest that the etiology of hyponatremia should change the rate of correction. Rapid correction is not recommended due to the potential for central pontine and extrapontine myelinolysis, collectively called osmotic demyelination syndrome (ODS).
Acute symptomatic hyponatremia is best corrected by hypertonic saline infusions.1 Hypovolemic hyponatremia is typically treated with 0.9% NaCl solution (Na+ = 154 mEq/L, Osm = 308) which is relatively hypertonic compared with the serum osmolality. This solution is expected to raise serum Na+ approximately 1 mEq/L for every 1 L of fluid. The Na+ deficit divided by the amount Na+ in 3% NaCl solution will determine the total volume to be infused. Estimates can be made using the equation:
This equation does not account for serum Na+ correction when there is a shift in body water, water excretion once euvolemia is restored, or when patients have SIADH.10 When treating euvolemic or hypervolemic hyponatremia, hypertonic saline 3% NaCl solution (Na+ = 513 mEq/L, Osm = 1027) should be used. The initial infusion rate can be estimated by calculated Na+ deficit.
Monitoring should include serum Na+ levels on a basic metabolic panel every 4 to 6 hours. Hypertonic therapy should be stopped if either the patient becomes asymptomatic, a safe serum Na+ >120 mEq/L is achieved, or a magnitude of correction of 18 mEq/L over 2 days is achieved. In short, hypertonic saline therapy should be discontinued when serum Na+ is in the safe range, which does not necessarily mean “normal” range.
Chronic hyponatremia should be treated by managing the underlying cause. SIADH should be treated with demeclocycline, a tetracycline derivative which inhibits the action of AVP causing a decrease in urine concentrations despite an increase in AVP levels. Demeclocycline can be dosed 900 to 12000 mg/d in 3 to 4 divided doses, and decreased as necessary. It can cause acute renal failure, especially in patients with liver disease, thus precluding its use.
Vasopressin receptor antagonists are a relatively new class of drug that exert their mechanism of action by inhibiting 1 of 3 subtypes of vasopressin receptors (Vsubtype) and prevent vasopressin activity. Vasopressin's physiologic action depends on the localization of the receptor. Vasopressin receptors V1A and V1B use the phosphoinositol pathway to increase cytosolic calcium for its second messenger, while V2 uses the adenylate cyclase pathway to increase cyclic adenosine monophosphate for its second messenger.11 V1A activation by vasopressin receptor sites can include vasoconstriction, platelet aggregation, ionotropic stimulation, and myocardial protein synthesis. V1B activation includes pituitary adrenocorticotrophic hormone secretion. V2 activation causes antidiuretic effects by activity on the renal collecting tubules, causing upregulation of aquaporins, and render the collecting duct permeable to water to allow water reabsorption.12 The ideal AVP receptor antagonists would increase Na+ free water clearance and overall show an increase in serum Na+ levels.
Conivaptan (Fig. 1) is nonpeptide benzazepin derivative of vasopressin, with a molecular weight of 535.04.13 Conivaptan is a white to off-white powder slightly soluble in water. The injection is supplied in a sterile premixed solution with dextrose in a flexible plastic container.13 It is a dual antagonist of the V1A and V2 vasopressin receptors. Conivaptan increases the excretion of free water by increasing urine output without increasing the Na+ output, thus normalizing the serum Na+ concentrations. Free water excretion translates to an increased net fluid loss, increased urine output, and decreased urine osmolality. Studies have assessed both the intravenous and oral formulations of conivaptan, but the manufacturer discontinued the oral formulation due to the potential for drug interactions associated with cytochrome P-450 enzyme inhibition.
Conivaptan exhibits nonlinear pharmacokinetics, primarily due to inhibition of its own metabolism, and high intersubject variability. Following the administration of a conivaptan 20 mg loading dose infused over 30 minutes, followed by a continuous infusion of 40 mg/d for 3 days in healthy male subjects, the mean peak conivaptan concentration was 619 ng/mL and occurred at the end of the loading dose. Minimum plasma concentrations occurred at approximately 12 hours after the start of the loading dose, and then gradually increased over the duration of the infusion to a mean concentration of 188 ng/mL at the end of the infusion. The mean terminal elimination half-life after the infusion was 5 hours, with a mean clearance of 15.2 L/h.13 An open label safety and efficacy study also assessed conivaptan in euvolemic and hypervolemic hyponatremic patients aged 20 to 92 years. Following a 20 mg loading dose and continuous infusion of 20 or 40 mg/d for 4 days, median conivaptan concentrations at the end of the loading dose were 659.4 ng/mL in the 20 mg/d group and 679.5 ng/mL in the 40 mg/d group. At the end of the 96 hours infusion, median conivaptan levels were 117.6 ng/mL in the 20 mg/d group and 215.7 ng/mL in the 40 mg/d group. The median elimination half-life was 5.3 hours in the 20 mg/d group and 8.1 hours in the 40 mg/d group. Clearance has ranged from 8.73 to 16.1 L/h.13
Conivaptan is extensively (99%) bound to plasma proteins, within the concentration range 10 to 1000 ng/mL. Conivaptan is solely metabolized by the cytochrome P-450 3A4 isozyme. Four metabolites have been identified, with 3% to 50% activity of conivaptan at the V1A receptor and 50% to 100% activity of conivaptan at the V2 receptors. Combined exposure to these metabolites is approximately 7% that of conivaptan, resulting in minimal clinical impact.13 Following intravenous administration, approximately 83% of the dose is excreted in the feces and 12% in the urine over several days. Approximately 1% of the dose is excreted in the urine unchanged. The pharmacokinetics of intravenous conivaptan have not been systematically studied in elderly patients or patients with renal or hepatic impairment.
Conivaptan was assessed in a randomized, double-blind, multicenter, placebo-controlled study enrolling 84 patients with euvolemic or hypervolemic hyponatremia (defined as serum Na+ 115 to >130 mEq/L). Therapy for hyponatremia included fluid restriction to <2 L per day plus either placebo or conivaptan for 4 days. Free water clearance after 1 day of treatment with a 20-mg intravenous loading dose followed by a 40 or 80 mg continuous infusion were 1953 and 1670 mL, respectively, compared with a reduction in free water clearance of 274 mL with placebo (P = 0.0004 and 0.0007).12 Serum Na+ increased by >6 mEq/L in a significantly greater percentage of patients on conivaptan 40 (69%) and 80 mg (88%) than placebo (21%) (P < 0.01 and <0.001, respectively). Effective water clearance was also increased to 1984 and 1759 mL, respectively, compared with a reduction of 322 mL with placebo (P = 0.0022 and 0.0012). Serum Na+ increased 6.4 mEq/L with the 40 mg/d dosage and 8.1 mEq/L with 80 mg/d (P = 0.0001 for both), compared with an increase of 0.4 mEq/L with placebo.14
Intravenous conivaptan was also assessed in an open-label study enrolling 104 patients with euvolemic hyponatremia. Patients were treated with conivaptan 20 or 40 mg/d as a continuous intravenous infusion following a 20-mg loading dose administered as a 30-minute infusion. Mean change in serum Na+ was 12.4 mEq/L for the conivaptan 20 mg/day group and 8.4 mEq/L for the conivaptan 40 mg per day group. The median time for increase in 4 mEq/L of serum Na+ was 12 hours for the 20 mg group, and 24.4 hours for the 40 mg group. Ninety percent of patients achieved a ≥6 mEq/L increase in serum Na+ or normal serum Na+ during treatment in the 20 mg group versus 73% in the 40 mg group.13
Oral conivaptan was studied in a multicentered, randomized, double-blind, placebo controlled trial.15 Patients were included if they were over 18 years with euvolemic or hypervolemic hyponatremia, defined as serum Na+ between 115 to 130 mEq/L. Patients were excluded if they had blood glucose >275 mg/dL, uncontrolled hypertension/ hypotension, hypothyroid, uncontrolled arrhythmias, adrenal insufficiency, creatinine clearance <20 mL/min, urinary outflow obstructions, or hepatic impairment. Patients received either conivaptan 40 mg, conivaptan 80 mg, or placebo, each in divided doses with fluid restriction of <2 L per day. Change in baseline of serum Na+ was significantly greater in the conivaptan group by 24 hours (P < 0.002) and sustained throughout the trial (P = 0.018). Serum area under the curve (AUC) of Na+ was also greater in the conivaptan group (P < 0.03). Median time to achieve an increase in serum Na+ of 4 mEq/L was shorter in the conivaptan group (P < 0.044). The mean change in serum Na+ was 6.4 mEq/L in the conivaptan 40 mg group, 8.2 mEq/L in the conivaptan 80 mg group, and 3.4 mEq/L in the placebo group (P = 0.002) at the end of treatment day 4. Normal serum Na+ or increase of 6 mEq/L was achieved in 71% of patients in the conivaptan 40 mg group, 82% in the conivaptan 80 mg group, and only 48% of patients receiving placebo (P = 0.014). No deaths were study related, and headache, hypotension, nausea, constipation, and postural hypotension occurred most frequently.15
One study evaluated intravenous conivaptan in patients with heart failure. This was a multicentered, randomized, double-blind, placebo controlled study.16 Patients were enrolled if they were over 18 years with New York Heart Association class II/III symptomatic heart failure due to left ventricular systolic dysfunction. Routine heart failure medications were allowed during the study, and included diuretics, angiotensin converting enzyme inhibitors, spironolactone, and beta-adrenergic blockers. Patients were excluded if the systolic blood pressure was <90 or if they had uncontrolled hypertension, uncontrolled arrhythmias, severe chronic obstructive pulmonary disease, congenital valvular disease, or significant renal impairment. Patients on inotropic agents were also excluded. Treatment included conivaptan 10 mg, 20 mg, 40 mg, or intravenous placebo over 30 minutes. Pulmonary capillary wedge pressure was significantly reduced in the conivaptan 20 and 40 mg compared with placebo (P < 0.05), which was sustained for 8 to 12 hours after drug administration. Right arterial pressures were also reduced in the conivaptan 20 and 40 mg group compared with placebo (P < 0.05). There were no statistically significant differences from placebo in cardiac index, pulmonary artery pressures, mean arterial pressures, pulmonary vascular resistance, or heart rate across the 4 groups. Urine output increased by 68.9 ± 17, 152.2 ± 19, and 176.2 ± 18 mL/h versus −11.3 ± 17 in the 3 conivaptan groups versus placebo, respectively.1
Conivaptan was also studied in 10 phase 2 pilot studies of patients with heart failure. There were no improvements in heart failure outcomes, such as decreased length of stay, categorized physical findings of heart failure, ejection fraction, exercise tolerance, functional status, or heart failure symptoms.13
Indications, Dosing, and Administration
Conivaptan (Vaprisol) is indicated for hospitalized patients with euvolemic or hypervolemic hyponatremia. Conivaptan therapy should be initiated with a loading dose of 20 mg administered intravenously over 30 minutes. The loading dose should be followed by 20 mg administered as a continuous infusion over 24 hours. Following the initial day of treatment, conivaptan should be administered for an additional 1 to 3 days as a continuous infusion of 20 mg/d. If serum Na+ is not rising at the desired rate, the conivaptan dose may be titrated to a dose of 40 mg daily. After the loading dose, the total duration of infusion should not exceed 4 days.
Conivaptan should be administered through large veins and the infusion site should be changed every 24 hours to minimize the risk of vascular irritation. Conivaptan no longer requires dilution prior to administration. It is now available in a premixed solution with 5% dextrose in water, not lactated ringers or sodium chloride.
Contraindication and Precautions
Conivaptan is contraindicated in patients with hypovolemic hyponatremia. It is also contraindicated as coadministration with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir. Conivaptan (Vaprisol) is premixed in 5% dextrose, which may be contraindicated in patients with known allergy to corn or corn products. Currently, there are too few patients treated with underlying congestive heart failure, hepatic impairment, or renal impairment to establish conivaptan's safety in these conditions. It is important to remember that overly rapid correction of serum Na+ may result in ODS and permanent neurologic sequelae. Conivaptan may also cause significant injection site reactions even with proper dilution and preparation.
The most common adverse effects with intravenous conivaptan administration were infusion site reactions. In studies with healthy volunteers and patients, 73% of subjects had injection site reactions when conivaptan 20 mg per day was used, 63% when using conivaptan 40 mg per day, and only 3% with placebo.13 In studies assessing oral conivaptan, headache, hypotension, nausea, constipation, and postural hypotension occurred more frequently than with placebo.15
Concomitant use of CYP3A4 inhibitors, such as ketoconazole, with conivaptan has been shown to result in a 4-fold increase in serum maximum concentration (Cmax) and an 11-fold increase in AUC. Conivaptan is also an inhibitor of CYP 3A4. Concomitant use of conivaptan with drugs metabolized by this isoenzyme may increase its concentration. Conivaptan 40 mg/d increased the mean AUC 2- to 3-fold with the use of midazolam 1 or 2 mg intravenous, respectively. Conivaptan 30 mg per day increased the AUC of simvastatin 2-fold, and oral conivaptan resulted in a 2-fold increase in amlodipine. Conivaptan is an inhibitor of p-glycoprotein, and may increase the Cmax and AUC of digoxin.
Conivaptan sterile liquid in ampules is no longer available. Conivaptan is now premixed with dextrose in a flexible plastic container. Each premixed solution of 100 mL contains 20 mg conivaptan hydrochloride, 5 g of dextrose, and lactic acid to adjust the pH.16 The cost of an intravenous bag is approximately $640.81 through wholesale distribution.
Tolvaptan (Fig. 2) is an orally active, nonpeptide, selective V2 receptor antagonist with a molecular weight of 448.9.17 Compared with native AVP, tolvaptan has 1.8 times greater affinity for the V2 receptor,17 in addition to a 29-fold greater selectivity for the V2 receptors than the V1a receptors. It has no inhibitory activity at V1b receptors.
Following oral administration, tolvaptan causes an increase in urine water excretion resulting in an increase in free water clearance, decreased urine osmolality, and increased Na+ concentration. Metabolites of tolvaptan have no activity at the V2 receptor.
The absolute bioavailability of tolvaptan following an oral dose is unknown, with at least 40% of the drug absorbed. Peak concentrations are reached in 2 to 4 hours, with no effect from food. The Cmax increases less than proportionally with doses, but the AUC increases proportionally. Tolvaptan is a substrate for p-glycoprotein and is highly protein bound (99%). The apparent volume of distribution is about 3 L/kg. Elimination is mainly nonrenal and tolvaptan is mainly metabolized by the CYP450 isoenzyme. Its terminal phase half-life is 12 hours. Moderate-to-severe hepatic impairment or congestive heart failure decreases the clearance and increases the volume of distribution, respectively, which is not clinically significant. Patients with creatinine clearance <10 mL/min were not studied.
The onset of aquaresis and Na+ increase is about 2 to 4 hours post dose, with the peak effect of increase in Na+ of 6 mEq/L and increase in urine output of 9 mL/min within 4 to 8 hours. At 24 hours, about 60% of the peak effect on Na+ is maintained, without continued aquaresis. Doses >60 mg/d do not increase the peak effect.
Tolvaptan was assessed in 2 identical multicenter, randomized, double-blinded, placebo-controlled studies enrolling 448 patients with euvolemic or hypervolemic hyponatremia (Study of Ascending Levels of Tolvaptan in Hyponatremia [SALT 1 and 2]).18 In these studies, patients were randomly assigned to receive tolvaptan 15 mg by mouth daily titrated up to 60 mg if necessary, or placebo by mouth daily. Eligible patients were 18 years and older with euvolemic and hypervolemic hyponatremia, defined as a serum Na+ <135 mEq/L, of diverse etiology. Patients with pychogenic polydipsia, head trauma, postoperative conditions, uncontrolled hypothyroidism, adrenal insufficiency, and medication-induced hyponatremia were excluded. Other exclusion criteria included the presence of ventricular arrhythmias, systolic blood pressure <90 mmHg, serum creatinine >3.5, Child-Pugh score >10, serum Na+ <120 mEq/L, uncontrolled diabetes, or other neurologic diseases. Patients were allowed to continue their heart failure regimen, and if the Na+ rose >145 or >12 mEq/L within 24 hours, the investigator withheld or decreased the next dose of tolvaptan or increased fluid intake. The increase in the average daily AUC for the Na+ concentration was significantly greater in the tolvaptan group than in the placebo group from baseline to study day 4, as well as during the entire 30-day study period (P < 0.001). Tolvaptan was also associated with a significantly greater increase in the average daily AUC for the serum Na+ concentration in subgroups stratified according to whether hyponatremia was mild <130 to 135 mEq/L or marked <130 mEq/L at baseline (P < 0.001). Within 8 hours after the first administration of tolvaptan, the serum Na+ concentrations were significantly higher in the tolvaptan group than in the placebo group for both the total patient population and the subgroups stratified by degree of hyponatremia at baseline (all P < 0.01). Significantly more patients in the tolvaptan-treated group had normal Na+ values at 30 days than placebo (53% and 58% vs. 25%) (P < 0.001). Urine output was significantly greater in the tolvaptan groups in both studies (P < 0.001). Fewer patients in both tolvaptan groups required fluid restriction (9.3% and 9.2% with tolvaptan compared with 17.5% and 16.8% with placebo). Improvement from baseline to day 30 in the tolvaptan group was also observed on the Mental Component Summary in the combined analysis (P = 0.02) and SALT-1 (P = 0.04), but not in SALT-2 (P = 0.14). The most common adverse events were thirst and dry mouth, with 11/26 serious adverse events occurring in the tolvaptan-treated patients. These events included dehydration-induced dizziness, dehydration-induced hypotension, acute renal failure, sepsis, and ascites.18 Upon discontinuation of treatment, patients' Na+ values declined in both the tolvaptan and placebo treatment groups and there was no statistical difference.
Tolvaptan was evaluated in a prospective, randomized, active-controlled, open-label trial to compare fluid restriction with the treatment of tolvaptan 10 to 60 mg daily.19 Patients were randomized 2:1 to therapy with tolvaptan or fluid restriction (1200 mL/d) plus placebo. The study was terminated prematurely due to enrollment difficulties and only 15 patients in the tolvaptan arm and 8 patients in the placebo arm were assessed. At 4 hours after the first dose, Na+ was increased by 1.6 mmol/L in the tolvaptan group and decreased by 0.8 mmol/L in the placebo plus fluid restriction group (P = 0.016). The primary end point, normalization of serum Na+ to >135 mmol/L or at least a 10% increase from baseline, was achieved in 11 tolvaptan-treated patients and 3 patients treated with fluid restriction (P = 0.049). Urine output was significantly greater in the tolvaptan-treated patients than the fluid restricted patients (P = 0.014). At the last inpatient visit, serum Na+ had increased by 5.7 mmol/L in the tolvaptan group and by 1 mmol/L in the fluid restriction group (P = 0.0065).19
Tolvaptan was studied in patients with heart failure (Table 1), 20–27 but has not received approval from the United States Food and Drug Administration for this indication.
Indications, Dosing, and Administration
Tolvaptan is indicated for patients with clinically significant euvolemic or hypervolemic hyponatremia defined as Na+ <125 mEq/L. It is also indicated for mild hyponatremia (Na+:125–135 mEq/L) in symptomatic patients, including patients with heart failure, cirrhosis, and SIADH that has resisted correction with fluid restriction.17 Tolvaptan should not be used in patients requiring intervention to urgently raise serum Na+ to prevent or treat neurologic symptoms.
The initiation of tolvaptan should only occur in a hospital setting to allow for monitoring of the therapeutic response and avoid the rapid correction of hyponatremia. The usual starting dose of tolvaptan is 15 mg by mouth once daily without regard to meals. Dose adjustments can be made after at least 24 hours, up to a maximum of 60 mg daily. Fluid restriction is not advised during the first 24 hours of therapy with the drug.
Dosage adjustment according to age, gender, race, cardiac, mild-to-severe renal, or hepatic function is not needed.17 Tolvaptan has not been studied in patients with creatinine clearance <10 mL/min or in patients undergoing dialysis. However, no benefit can be expected in anuric patients.
Contraindication and Precautions
Tolvaptan is contraindicated in patients with an urgent need to raise serum Na+, with an inability to sense thirst or appropriately respond to thirst, and in patients with hypovolemic hyponatremia. There is not enough experience to define the dosage adjustments of tolvaptan needed with concomitant CYP 3A4 inhibitors, as such patient response should be monitored closely and doses of tolvaptan adjusted accordingly. No clinical benefit can be expected in patients unable to make urine. Caution should be taken to avoid too rapid correction of serum Na+ that may cause serious neurologic sequelae.
Cirrhotic patients treated with tolvaptan experience higher rates of gastrointestinal bleeding than patients receiving placebo (10% vs. 2%).17 There is no experience using hypertonic saline and tolvaptan concomitantly.
Two 30-day clinical trials consisting of 650 patients with hyponatremia assessed adverse reactions. Common adverse drug reactions, defined as a 5% greater incidence than placebo, were thirst, dry mouth, asthenia, constipation, and pollakiuria.17 Ten percent of tolvaptan-treated patients discontinued treatment, compared with 12% of placebo-treated patients.
Tolvaptan is metabolized by CYP 3A4. Strong inhibitors of CYP3A4, such as ketoconazole and clarithromycin, increase exposure 5-fold, while CYP3A4 inducers, such as rifampin, decrease plasma concentrations of tolvaptan by 85%. Concomitant therapy with these agents should be avoided if possible. Concomitant use of tolvaptan with weak-to-moderate inhibitors of CYP3A4 has not been assessed. Tolvaptan is also a substrate and inhibitor of p-glycoprotein. Coadministration with inhibitors of p-glycoprotein, such as cyclosporine, may require a decrease in the tolvaptan dose. Tolvaptan may increase plasma levels of digoxin, which is a substrate of p-glycoprotein.
Tolvaptan is available as a nonscored 15-mg triangular and 30-mg round tablet. Tolvaptan should be stored at controlled room temperature (59°F-86°F). The unit cost of tolvaptan is $3050.00 per 10-tablet packet through wholesale distribution.
AVP antagonists predictably increase aquaresis and serum Na+ in patients with euvolemic and hypervolemic hyponatremia. In the United States, only conivaptan, a nonselective intravenous AVP antagonist, and tolvaptan, a V2 selective oral AVP antagonist are commercially available. Other AVP antagonists, such as lixivaptan and satavaptan, are V2 selective oral agents being studied for hyponatremia, but not commercially available in the United States.
Conivaptan seems to be a good intravenous agent in hospitalized patients with euvolemic or hypervolemic hyponatremia due to its formulation and rapid peak activity at 1 to 2 hours. Tolvaptan is not ideal in the acute setting due to its oral formulation and delayed peak at 4 to 8 hours. Despite their novel mechanism of action, neither of the agents have evidence to suggest that AVP antagonists alone are sufficient to raise serum Na+ levels enough for acute severe hyponatremia with neurologic signs and symptoms. Hypertonic saline remains the gold standard for all acutely ill patients with neurologic manifestations of hyponatremia, and unfortunately neither agent has been studied with hypertonic saline, to date. Using AVP antagonists for hyponatremia in acutely ill patients is difficult to justify, especially when the average daily cost of tolvaptan alone is $305, and conivaptan alone is $640.
All hospital trials showed an overall correction of serum Na+ in a majority of patients during the AVP antagonist treatment. Outpatient trials of tolvaptan also showed correction of serum Na+, although this was not the primary objective of these trials. SALT 1 and SALT 2 trials evaluating tolvaptan therapy suggest that this increase in serum Na+ may not be sustained when using AVP antagonists, since serum Na+ levels fall within 7 days after discontinuation of therapy. These studies also emphasize the need for correction of the underlying cause of hyponatremia if clinically feasible.
Both conivaptan and tolvaptan are safe agents to be used in the treatment of clinically significant euvolemic and hypervolemic hyponatremia. Neither drug caused ODS, and the most common adverse events were dry mouth and thirst. Both drugs should be used with caution in patients receiving CYP 3A4 inhibitors, and in patients with hepatic and renal impairment.
In all, there is no clear mortality benefit in using these agents for hyponatremia over the standard of care. Tolvaptan has been extensively studied for improvements in heart failure parameters, and has been clinically shown to decrease body weight, edema, and dyspnea. Currently, tolvaptan is not indicated for heart failure. One multicentered, randomized, placebo-controlled study in patients with heart failure assessed mortality and rehospitalization due to heart failure.24 This study showed favorable outcomes with 1 year of tolvaptan use versus placebo in the time-to-event analysis. There were no clear favorable effects on measures of ventricular remodeling, and the outcome events were investigator reported, not a prespecified end-point adjudicated by the blinded central events committee. This finding was incidental and hypothesis generating, even though the investigators where blinded. The EVEREST trial evaluated long-term outcomes, and showed no effect on mortality or heart failure morbidity when initiated for acute treatment in hospitalized patients with heart failure.26
Future studies are needed to determine the appropriate use for this indication as well as in patients having hyponatremia and ascites related to cirrhosis.
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