9/30/2010 JAMES S. KALUS, PHARM.D, BCPS (AQ-CARDIOLOGY) Senior Manager, Patient Care Services, Department of Pharmacy Services Henry Ford Hospital, Detroit, MI NO RELATIONSHIPS TO DISCLOSE J. HERBERT PATTERSON, PHARM.D, Professor of Pharmacy Research Professor of Medicine Vice Chair for Research and Graduate Education UNC Eshelman School of Pharmacy Friday, October 1, 2010 University of North Carolina, Chapel Hill, NC Advisory Board Member Otsuka America Pharmaceuticals Inc.* *Conflict was resolved through Peer Review Learning Objectives • Describe the underlying pathophysiology, risk factors, and risk stratification of hospitalized patients with hyponatremia • Identify the mechanisms in which hyponatremia PLEASE TAKE A MOMENT TO ANSWER comppglicates the management of chronic medical THE PRE-ACTIVITY TEST QUESTIONS conditions • Assess the pharmacists role and current treatment options for hyponatremia in the hospital setting. • Examine the role of vasopressin receptor antagonists in the management of hyponatremia in the hospitalized patient Hyponatremia • Most common electrolyte abnormality Hyponatremia can be • Associated with many systemic diseases caused by dilution from – Major: dilution of extracellular fluid retained water, or by – Minor: total body losses of sodium dltidepletion fltltfrom electrolyte • Acute vs. Chronic losses in excess of water – Often duration is difficult to determine 1 9/30/2010 Role of Vasopressin Role of Vasopressin • Vasopressin = ADH = antidiuretic hormone Nephron • Physiologic sodium/water balance – Thirst: stimulated by rise in osmolality H O • Osmoreceptors 2 Vasopressin – Water excretion: regulated by vasopressin H2O • Osmoreceptors H2O – ↑ Osmolality = ↑ vasopressin secretion = ↑ H2O reabsorption Vasopressin – ↓ Osmolality = ↓ vasopressin secretion = ↓ H2O reabsorption = V2 Receptors AVP regulation of water reabsorption from renal tubular cells Classification: Osmolality CollectingDuct Cell AQP3 Collecting duc • Hypotonic hyponatremia – Sodium directly related to osmolality H2O – Most cases Vasa recta Vasa ATP GTP AQP2 Exocytic • Isotonic/Hypertonic hyponatremia AVP Insertion t (Gs) cAMP – Pseudohyponatremia AVP V2 Receptor PKA – Non-sodium solutes increase osmolality H2O AQP2 • Glucose • ↑ osmolality Æ fluid shifts Æ dilution of sodium Recycling Endocytic vesicle Retrieval AQP4 Basolateral Luminal membrane membrane Prevalence of dysnatremias at initial Classification: Volume Status presentation to a health care provider (data from 303,577 samples on 120,137 patients available for analysis) HYPONATREMIA HYPOVOLEMIC EUVOLEMIC HYPERVOLEMIC Na+ Loss Non-Physiologic ↑ Volume Release of ADH Diuretics Heart Failure SIADH Mineralocorticoid Liver Disease Deficiency Kidney Disease Glucosuria Ketonuria Vomiting Diarrhea Adapted from: Hawkins RC. Clin Chim Acta..2003; 337(1-2):169-72. 2 9/30/2010 Drug-Related Causes Risk Stratification Sodium Loss • Acute vs. Chronic • Diuretics – Acute = less than 48 hours in duration • Concerned about neurologic sequellae – Osmotic differential between brain and blood – Brain swelling ↑ Vasopressin/ADH effects – Chronic = greater than 48 hours in duration • Symptoms may be more modest • Antipsychotics – Brain has time to adapt • Antidepressants • Duration of hyponatremia • DDAVP – How aggressive? • Oxytocin – How fast? Discussion Question Discussion Question - ANSWER Common symptoms of chronic Common symptoms of chronic hyponatremia include fatigue, nausea, hyponatremia include fatigue, nausea, dizziness, lethargy, confusion, and gait dizziness, lethargy, confusion, and gait disturbances? disturbances? A. True A. True B. False B. False Symptomatic Hyponatremia: Symptoms Associated with Chronic Neurological Manifestations Hyponatremia 223 consecutive hospitalized patients with symptomatic • Headache hyponatremia ([Na+] 98 to 128 mmol/l) due to thiazides • Irritability • Malaise/Lethargy: 109 (49%) Nausea/Vomiting • Chronic • Dizzy Spells: 104 (47%) 223/223 resolved Mental Slowing symptoms with • • Vomiting: 77 (35%) correction of [Na+] • Confusion/Delirium • Confusion/Obtundation: 39 (17%) via cessation of thiazide treatment • Disorientation • Falls: 37 (17%) • Headache: 13 (6%) • Stupor/Coma • Seizures: 2 (0.9%) • Convulsions Acute • Respiratory Arrest Chow KM, et al. J Natl Med Assoc. 2004; 96:1305-1309. 3 9/30/2010 Increased Risk of Falls with Sodium and the Brain “Asymptomatic” Hyponatremia Na+ moves from high concentrations to low Adjusted + Odds Water follows Na Group n Falls Odds Ratio Time-dependent Ratio* 9.45 67.43 + + “Asymptomatic”Chronic + 122 21.3% (2.64-34.09) (7.48-607.42) + Hyponatremia + p <.001 p <.001 + + + + + Normonatremic controls 244 5.35% 1.00 1.00 + + + + + + + + + *adjusted for age, sex and covariates BRAIN EDEMA Adapted from: Renneboog B, et al. Am J Med. 2006;119(1): 71. e1-8. Reductions of Brain Organic Osmolytes after 14 days of Sustained Hyponatremia Discussion Question The hyponatremic brain is NOT a normal brain, but rather There is less likelihood of rapid fluid represents a state of allostasis -30% as a result of solute losses shifts and brain edema in cases of acute hyponatremia than there are in cases ofhf chron ihic hypona trem ia A. True B. False *P < 0.01 compared to normonatremic control rats. Adapted from: Verbalis JG, et al. Brain Res. 1991; 567(2):274-82. Discussion Question - ANSWER Acute vs. Chronic and the Brain There is less likelihood of rapid fluid • Acute hyponatremia shifts and brain edema in cases of – Rapid onset acute hyponatremia than there are in – Greater likelihood of rapid fluid shifts and brain edema cases ofhf chron ihic hypona trem ia • Chronic hyponatremia A. True – Insidious onset B. False – Less likelihood for brain edema • Time for compensatory increases in organic osmolytes 4 9/30/2010 How Aggressive? How Fast? Sodium and the Brain LEVEL 3 - SEVERE SYMPTOMS: Na+ moves from high concentrations to low vomiting, seizures, obtundation, Emergency! Correct RAPIDLY Water follows Na+ respiratory distress, coma Implications for treatment LEVEL 2 - MODERATE + + + SYMPTOMS: + nausea, confusion, disorientation, + altered mental status + ++ + + + + + LEVEL 1 - NO OR MINIMAL + + SYMPTOMS: + headache, irritability, inability to OK to correct more slowly concentrate, altered mood, depression Rapid fluid shifts out of the brain: OSMOTIC DEMYELINATION Implications of Hyponatremia Heart failure • There are an estimated 7 million Americans with Hyponatremia HF (2% of US population). and Heart Failure • Hyponatremia is one of the newer and emerging risk factors for an adverse prognosis in chronic heart failure • Increased release of vasopressin may result in excess fluid retention and hyponatremia. Implications of Hyponatremia Liver Disease • Associated with poor prognosis & reduced Hyponatremia survival • Impairs the management of ascites and Liver Disease • Predisposes to hepatic encephalopathy • Impairs quality of life 5 9/30/2010 Pathogenesis of Hyponatremia in Cirrhosis Distribution of serum sodium in patients Systemic arterial vasodilatation with liver cirrhosis & ascites (n=983) Sinusoidal portal hypertension Severe liver dysfunction % Hyperdynamic ↑total body blood volume, but circulation ++ 40 ↓↓EABV 35.1 35 27.9 ActActivationivation ooff RAARAASS & SSNSNS ++ 30 Diuretic responsive Non-osmotic release of vasopressin ↓ 25 Diuretic resistant 20 15.8 15 11.1 Severe renal Na retention 10 proximal > distal tubular 4.5 4.4 5 1.3 Water retention follows Na retention 0 </=120 121-125 126-130 131-135 136-140 141-145 >145 serum sodium (mEq/L) When water retention> Na retention, hyponatremia develops Adapted from P.Angeli et al. Hepatology 2006; 44:1535-1542 Serum Sodium and Mortality Liver Transplant candidates in the VA system, 97-03 (n= 507) ̵ Hepatitis C (68%), EtOH (67%) ̵ MELD 16.2 + 6.7 ̵ Hyponatremia (<130 mEq/L): 31% ̵ Persistent Ascites/Hydrothorax: 38% Syndrome of inappropriate • Predictors of 6-month mortality antidiuretic hormone (()SIADH) Odds Ratio p secretion MELD 1.25 (1.16-1.35) <0.001 Na < 135 mEq/L 2.76 (1.31-5.81) 0.008 Persistent 2.72 (1.31-5.71) 0.008 Ascites Heuman DM, et al. Hepatology. 2004;40(4):802-10. Syndrome of Inappropriate Anti-diuretic Causes of Syndrome of Inappropriate Hormone (SIADH): Essential Criteria Anti-diuretic Hormone (SIADH): Pulmonary Disorders Tumors CNS Disorders Acute respiratory failure Extrathoracic Acute psychosis • True plasma hypoosmolality Infections Mediastinal Hemorrhage Positive-pressure ventilation Pulmonary Inflammatory and Urine concentration inappropriate for plasma demyelinating diseases • Mass lesions Stroke osmolality (Uosm > 100 mOsm/kg H2O) SIADH Trauma • Clinical euvolemia, no diuretic therapy Drugs • Absent renal sodium conservation (UNa > 30 Carbamazepine Phenothiazines Miscellaneous Chlorpropamide Prostaglandin-synthesis HIV infection mmol/L) Clofibrate inhibitors Idiopathic Cyclophosphamide SSRIs Pain Desmopressin MAO inhibitors Postoperative state • Normal thyroid, adrenal and renal function Nicotine Tricyclics Prolonged exercise Oxytocin Vincristine Senile atrophy Opiates Severe nausea Bartter FC, et al. Am J Med. 1967; 42:790-806. 6 9/30/2010 Conclusions – Hyponatremia is a common disorder of electrolytes seen in the hospital setting. – Acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with co morbidities. – Overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death. – SIADH is the most common cause of euvolemic hyponatremia in clinical medicine. – Hypervolemic