Empowering Pharmacists to Improve Management of Hyponatremia. Learning Objectives. Diagnostic Algorithm for Hyponatremia

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1 Empowering Pharmacists to Improve Management of Hyponatremia A Patient-Centric, Process of Care Guide Learning Objectives Discuss the clinical consequences of undertreatment of hyponatremia, including clinical manifestation, related comorbidities and clinical and resource burden Describe the pathophysiology of hyponatremia, including euvolemic hyponatremia in SIADH and hypervolemic hyponatremia in heart failure Classify patients with hyponatremia based on clinical presentation and comorbidities and recommend appropriate correction therapy Outline current recommendations and guidelines for the treatment of hyponatremia Summarize the pathophysiology of disease and related mechanismsof-action, efficacy and safety/tolerability evidence for hyponatremia pharmacotherapies Identify and commit to three or more practice improvements pharmacists can make to improve the process of care for hyponatremia Diagnostic Algorithm for Hyponatremia Assessment of volume status Hypovolemia Total body water Total body Na+ Euvolemia (no edema) Total body water Total body Na+ Hypervolemia Total body water Total body Na+ U [Na+] >20 meq/l U [Na+] <20 meq/l U [Na+] >20 meq/l U [Na+] >20 meq/l U [Na+] <20 meq/l Renal Losses Diuretic excess Mineral corticoid deficiency Salt-losing deficiency Bicarbonaturia with renal tubal acidosis and metabolic alkalosis Ketonuria Osmotic diuresis Extrarenal Losses Vomiting Diarrhea Third spacing of fluids Burns Pancreatitis Trauma Glucocorticoid deficiency Hypothyroidism SIADH secretion Drug-induced stress Acute or chronic renal failure Nephrotic syndrome Cirrhosis Cardiac failure Legend: increase; greater increase; decrease; greater decrease; no change SIADH = syndrome of inappropriate antidiuretic hormone. Adapted from Kumar S, Beri T. Diseases of water metabolism. In: Berl T, Bonventre JV, eds. Atlas of Diseases of the Kidney. Vol. 1. Philadelphia, PA: Current Medicine, Inc; 1999:

2 AVP Release and Sites of Action Posterior pituitary AVP release Anxiety and stress (V 1 ) Myocyte hypertrophy (V 1 ) Glycogenolysis (V 1 ) Vascular tone: Vasoconstriction (V 1 ) Vasodilation (V 2 ) Blood: Platelet aggregation (V 1 ) Von Willebrand factor (V 2 ) Body fluid: Water retention (V 2 ) AVP = arginine vasopressin. Adapted from Ferguson JW, et al. Clin Sci (Lond). 2003;105(1):1-8. AVP Regulation of Water Reabsorption from Renal Tubular Cells Vasa recta AVP AQP3 GTP (Gs) AVP V 2 receptor AQP4 Basolateral membrane Collecting Duct Cell ATP camp PKA AQP2 Recycling vesicle Exocytic insertion H 2 O Collecting duct H 2 O AQP2 Endocytic retrieval Luminal membrane AQP = aquaporin; GTP = guanine nucleotide binding protein; ATP = adenosine triphosphate; camp = cyclic adenosine monophosphate; PKA = protein kinase A. Mayinger B, et al. Exp Clin Endocrinol Diabetes. 1999;107(3): Risk Stratification First Decision: Presentation Acute vs. Chronic? How aggressive? How fast? Second Decision: Duration of hyponatremia Acute = less than 48 hours in duration Concerned about neurologic sequellae Osmotic differential between brain and blood Brain swelling Chronic = greater than 48 hours in duration Symptoms may be more modest Brain has time to adapt

3 Hyponatremia Treatment Options LEVEL 3 - SEVERE SYMPTOMS: vomiting, seizures, obtundation, respiratory distress, coma Hypertonic Saline LEVEL 2 - MODERATE SYMPTOMS: nausea, confusion, disorientation, altered mental status Vasopressin Antagonist or Hypertonic Saline *** LEVEL 1 - NO OR MINIMAL SYMPTOMS: headache, irritability, inability to concentrate, altered mood, depression Fluid restriction Consider vasopressin antagonist or hypertonic saline if Unable to tolerate fluid restriction or failure of fluid restriction Need for rapid correction of Na + *** Vasopressin antagonists may be preferred if volume overloaded Traditional Pharmacological Treatment Strategies Text Footnotes and references. This refuses to adhere to a template. Copy and paste this text box into whatever slides need it, and replace the text. Traditional Pharmacological Treatment Strategies

4 Hyponatremia: Practical Approach on the Use of Hypertonic Saline Comparison of Sodium Chloride Injection Drug Facts and Comparisons St. Louis, MO: Wolters Kluwer Health; Rate of Sodium Correction Initial rate of sodium correction not to exceed 1-2 meq/l/hr High risk of Osmotic Demyelination Syndrome (ODS) do not exceed 8 meq/l in 24 hours Hypokalemia, alcoholism, malnutrition,advanced liver disease or serum sodium < 105mEq/L Normal risk of ODS rate of sodium correction should be limited to < 12 meq / L /24 hr or 18 meq/l in 1st 48 hr Verbalis JG et al. Amer J Med 2013;126, S1-S42. Laureno R et al. Ann Intern Med 1997;126: Cawley MJ. Ann Pharmacotherapy 2007;41:840-50

5 Calculation of Sodium Requirement: Adrogué-Madias Equation Change in serum sodium = infusate Na serum Na TBW + 1 Infusate Na = sodium concentration of infusate 0.9% (154mEq/L); 3% (513mEq/L) Serum Na = patient s serum sodium concentration TBW = total body water = weight x correction factor (Correction factor of 0.6 L/kg men, 0.45 L/kg women) 1 = 1 liter of solution Adrogue HJ et al. N Engl J Med 2000;342: Calculation Example 70-kg unresponsive male, serum sodium 110 meq/l If 1 L of 3% sodium chloride injection is administered how much of a change in serum sodium will occur? Infusate Na (3%) = 513 meq/l Patient s serum Na = 110mEq/L TBW = 0.6 L/kg x 70 kg Change in serum sodium = infusate Na serum Na TBW + 1 Change in serum sodium = 9.4 meq/l Calculation Continued Estimated effect of 1 liter of 3% sodium chloride would be 9.4 meq/l or 0.94 meq per 100 ml How do you administer the infusate? Calculate total volume to administer in 24 hr, given 12 meq/l is max increase in serum Na in 24 hr 100 ml x 12 meq/l = 1,277mL 0.94 meq/l Calculate recommended rate of infusion 100 ml x 1.5 meq/l/hr* = 160 ml/hr 1 st 4 hr 0.94 meq/l ~32 ml/hr for 20 hr * Recommended rate of sodium correction for severe symptoms at normal risk for ODS

6 Calculation Continued Calculation of infusion rate Multiply body weight in kg by desired rate of increase in sodium in meq/l/hr (ex., 70kg patient, a 3% NaCl infusion at 70 ml/hr will increase sodium ~1 meq/l/hr, while infusing 35ml/hr will increase serum sodium ~0.5 meq/l/hr) Monitor sodium levels frequently (q 4-6 hr) Rate of Sodium Correction is more important than the infusion rate.. Verbalis JG et al. The Amer J Med 2013;126:S1-S42. Ellison DH et al. N Engl J Med 2007;356: Hyponatremia Patient Case Study Heart Failure Hyponatremia in Heart Failure Admission Serum Sodium [Na + ] < 135 meq/l [Na + ] 135 meq/l 42.5 P < P < P < P < LOS (days) In-Hospital Mortality (%) Post-Discharge Mortality (%) Death or Rehospitalization Since Discharge (%) 1. Gheorghiade et al. Eur Heart J. 2007;28: Gheorghiade et al. Arch Intern Med. 2007;167: Gheorghiade et al. JAMA. 2004;291(16): Klein et al. Circulation. 2005;111:

7 Survival in HF Decreased with Concomitant Hyponatremia* Cumulative Probability of Death Log-rank P< Sodium Level <136 meq/l Sodium Level 136 meq/l Number at Risk Time (days) Sodium Level <136 meq/l Sodium Level meq/l *Survival rates were significantly reduced if patients with acute ST-elevation myocardial infarction had concomitant hyponatremia ([Na+] <135 meq/l) on admission (P<.0001). Adapted from Goldberg A, et al. Arch Intern Med. 2006;166(7): Patient Chart Overview John is a 78-year-old, 75 kg hispanic male admitted to the CCU in acute decompensated heart failure. He has been extremely fatigued with SOB for several weeks prior to admission. After 6 days of treatment the patient is now receiving intravenous diuretics and vasodilator therapy and is now moved to a step down unit for medication stabilization prior to discharge. Medical history Ischemic cardiomyopathy (LVEF 23%) s/p AMI x 2 in 2007 and 2010 HTN x 35 years Hyperlipidemia x 32 years Osteoporosis x 20 years CCU = coronary care unit; LVEF = left ventricular ejection fraction Patient Chart Overview Family history Unremarkable Social history Smokes 1.5 packs per day x 29 years (D/C 5 years) No alcohol use Physical assessment Vital signs: HR: 92 bpm, BP: 116/82 mm Hg, RR: 14 bpm, Temp: 38.9 C Weight: 81 kg (dry weight 77 Kg), Height: 157 cm Chest: Crackles bilateral bases Abdomen: Distended Skin: + 2 pitting edema in both arms and legs Neurologic Cranial nerves II-VIII grossly intact A&O x 3 HR = heart rate; BP = blood pressure; RR = respiratory rate; bpm = breaths per minute; A&O = alert and oriented.

8 Patient Chart Overview Laboratory (day 7 of admission) Serum sodium: 125 meq/l Serum osmolality: 264 mosm/kg Urine sodium: 18 meq/l Urine osmolality: 255 mosm/kg Serum creatinine: 1.2 mg/dl Intake/output (total over 7 days) 5360 ml/3200 ml ( ml) Current medications Furosemide 40 mg IV every 8 hours Lisinopril 5 mg qday Carvedilol 6.25 mg BID Spironolactone 12.5 mg by mouth daily Optimal Treatment Strategies AGENT Fluid restriction Diuretics Demeclocycline Oral Sodium Chloride LIMITATIONS Slow to correct over days (1-2 meq/l/day) Poorly tolerated due to thirst Should not be used with high AVP level and urine osmolality Allows relaxation of fluid restriction Potential for ototoxicity, volume depletion, and K + and Mg + depletion Not FDA approved for hyponatremia Slow to correct over days Nephrotoxic in cirrhosis and heart failure Nausea and vomiting Rarely can give large enough dose to be effective No data Optimal Treatment Strategies AGENT Isotonic saline Hypertonic saline LIMITATIONS Ineffective in dilutional hyponatremia Should not be used in setting of edema No safety data Complex calculations No consensus regarding appropriate infusion rates Overcorrection can cause osmotic demyelination syndrome Should not be used in setting of edema No safety data Complex calculations

9 Optimal Treatment Strategies AGENT Standard Heart Failure Treatment Measures OPTIONS Consider Increase in ACEi dose Consider increase in Carvedilol dose Vaptan Clinical Considerations Tolvaptan Indicated for clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 meq/l or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with HF, cirrhosis, and SIADH Available in 15-mg and 30-mg tablets Dosing: 15 mg orally once daily. Dosing may be increased at intervals 24 hours to 30 mg once daily to a maximum of 60 mg once daily Should only be initiated and re-initiated in a hospital setting. Healthcare providers must review the FDA-approved medication guide with every patient Coadministration with potent CYP3A4 enzyme inhibitors (ketoconazole, itraconazole, indinavir) is contraindicated Tolvaptan [package insert]. Rockville, MD: Otsuka America Pharmaceutical, Inc; Vaptan Clinical Considerations Conivaptan Indicated for euvolemic/hypervolemic hyponatremia in hospitalized patients Administer IV via large veins due to infusion-site reactions (63% to 73%) Change infusion site every 24 h Hypervolemic hyponatremia associated with heart failure: Data are limited. Use other treatment options Dosing: 20 mg IV 30min followed by 20 mg as a continuous 24 h Duration of infusion limited to 4 days Limited data on drug-drug compatibility Contraindicated with potent CYP3A4 enzyme inhibitors (ketoconazole, itraconazole, indinavir) Conivaptan [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2010.

10 Hyponatremia Treatment Options LEVEL 3 - SEVERE SYMPTOMS: vomiting, seizures, obtundation, respiratory distress, coma Hypertonic Saline LEVEL 2 - MODERATE SYMPTOMS: nausea, confusion, disorientation, altered mental status Vasopressin Antagonist or Hypertonic Saline *** LEVEL 1 - NO OR MINIMAL SYMPTOMS: headache, irritability, inability to concentrate, altered mood, depression Fluid restriction Consider vasopressin antagonist or hypertonic saline if Unable to tolerate fluid restriction or failure of fluid restriction Need for rapid correction of Na + *** Vasopressin antagonists may be preferred if volume overloaded Hyponatremia Patient Case Study Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Causes of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Upadhyay A et al. Sem Nephrol 2009;29:

11 Recognition of SIADH Hyponatremia with low serum osmolality Excessive renal excretion of sodium (> 20mEq/L) Limited clinical evidence of volume depletion or overload Normal skin turgor and blood pressure (euvolemia) Normal renal, adrenal and thyroid function Bartter FC, et al. Am J Med 1967;42: Patient Case Rebecca is a 67 year-old female who presents to the ED with her husband who states my wife has become more confused and forgetful over the past hours Medical History HTN x 16 years COPD x 10 years Osteoporosis x 11 years Depression diagnosed 4 weeks ago Patient Case Family history Unknown Social history (-) alcohol, (-) tobacco, (-) IVDA Physical assessment Vital signs: HR: 84bpm, BP 128/82mmHg, RR: 12BPM, Temp: 98.6F Weight: 61kg (admission weight), Height: 167cm General Confused Chest Clear A & P Abdomen Unremarkable Skin Unremarkable Neurologic Cranial nerves II-VIII grossly intact A & O x 1 (person) HR= heart rate; BP = blood pressure; RR = respiratory rate; bpm = breaths per minute; A7O = alert and oriented

12 Patient Case Laboratory (admission) Serum sodium 112 meq/l Serum osmolality 265 mosm/kg Urine sodium 25 meq/l Serum creatinine 1.1 mg/dl Current medications Tiotropium bromide 18 mcg capsule 2 inhalation of one capsule, once daily with HandiHaler device Cardizem 240mg by mouth daily x 8 yrs HCTZ 25 mg by mouth daily x 5 years Oscal 600mg by mouth twice daily x 10 years Venlafaxine 100mg by mouth daily x 30 days Drug-Induced Hyponatremia (SIADH) Risk factors for the development of hyponatremia with SSRI s: Older age Female gender Concomitant use of diuretics Lower body weight Lower baseline serum sodium level Hyponatremia develops within weeks of treatment and resolves after two weeks after therapy discontinued Treatment for severe hyponatremia includes hypertonic saline +/- loop diuretic Jacob S, et al. Annals of Pharmacotherapy 2006;40: Drug-Induced Hyponatremia (SIADH) Retrospective controlled study 199 elderly psychiatric inpatients (mean age 74.2 years) 74 prescribed SSRI or venlafaxine 10 of 14 patients on venlafaxine developed hyponatremia 39% of patients on an SSRI or venlafaxine had hyponatremia vs 10% of controls Elderly patients on SSRI or venlafaxine should have serum sodium levels checked before and after commencement of antidepressant therapy Kirby D et al. Int Geriatr Psychiatry 2002;17:231-7.

13 Potential Risk of Liver Injury with Tolvaptan Double blind, 3 year placebo controlled trial in 1445 patients with Autosomal Dominant Polycystic Kidney Disease 3 patients significant increases in ALT and Tbili 4.4% (42/958) on tolvaptan and 1% (5/484) on placebo exhibited greater than 3x ULN of ALT Maximum daily dose was 90mg morning and 30mg in afternoon which is higher than 60mg daily for hyponatremia Previous trials did not identify liver damage with tolvaptan Reduce the risk of new liver injury by limiting duration of therapy ALT- Alanine aminotransferase, Tbil Total bilirubin, ULN Upper limit of normal Torres VE et al. N Engl J Med 2012;367: Tolvaptan Safety Increased liver enzymes suggestive of liver injury All 3 patients with liver enzyme abnormalities improved after tolvaptan was discontinued This finding of liver injury prompted an FDA alert: Tolvaptan should be avoided in patients with underlying liver disease, including cirrhosis. Warning that patients on tolvaptan who exhibit any symptoms suggestive of liver disease should undergo liver tests and that tolvaptan should be stopped immediately if liver injury is suspected Warnings include limiting the treatment duration to no more than 30 days and to avoid use in patients with liver disease m htm. Accessed February 2014 U.S. Guidelines and European Guidelines Hyponatremia Classification Hypovolemic hyponatremia Euvolemic hyponatremia, Asymptomatic Euvolemic hyponatremia, Moderate to severe CNS symptoms Hypervolemic hyponatremia Asymptomatic Hypervolemic hyponatremia Moderate to severe CNS symptoms U.S. Expert Panel Recommendations Vaptan is NOT a treatment option Vaptan is a treatment option Vaptan is NOT a treatment option Vaptan is a treatment option (NOT for those with liver disease) Vaptan is NOT a treatment option European Clinical Practice Guideline Vaptan NOT a treatment option Do NOT recommend vaptan Recommend AGAINST vaptan Recommend AGAINST vaptan Recommend AGAINST vaptan Verbalis JG, et al. Am J Med. 2013;126(10 suppl 1):S1-S42. Spasovski G, et al. Eur J Endocrinol. 2014;170(3):G1-G47.

14 Practical Considerations for the Use of Tolvaptan* LFT s and/or Tbili levels > 2x upper limit of normal avoid starting drug LFT s and/or Tbili levels 2x upper limit of normal during treatment would discontinue drug (drug or disease etiology?) Monitor LFTs and/or Tbili weekly until normal When Tolvaptan is not an option: Low sodium diet + spironolactone Fluid restriction Loop diuretic Paracentesis Transjugular intrahepatic portosystemic shunt (TIPS) * Recommendations only based upon clinical experience. These recommendations are not endorsed by NACCME or Otsuka America Pharmaceuticals Pharmacist Roles and Responsibilities Monitor for hyponatremia Consider drug related causes Educate clinicians on hyponatremia Optimize selection of pharmacological treatments Maintain vigilance in monitoring during treatment Protocol development Conclusion Hyponatremia is associated with increased mortality and increase in economic impact. The presence or absence of significant neurologic signs and symptoms is very important in guiding therapy. Overly aggressive rapid correction of hyponatremia can result in osmotic demyelination syndrome. An increase in serum [Na+] should be limited to: <12 meq/l/24 hours or 18 meq/l in 1 st 48 hrs for normal risk of ODS < 8 meq/l/24 hours if at high risk of ODS Pharmacists have an increased role and responsibility in caring for the patient with hyponatremia