HYPONATREMIA BY PROBABLE DRUG INTERACTION BETWEEN SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND DIURET
HYPONATREMIA BY PROBABLE DRUG INTERACTION BETWEEN SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND DIURETICS Douglas Dogol Sucar (1), Everton Botelho Sougey (1) (1)Postgraduate Program in Neuropsychiatry and Behavioral Sciences, Department of Neuropsychiatry, Federal University of Pernambuco, Recife, Brazil BACKGROUND Hyponatremia is a complex, clinically relevant occurrence that is difficult to diagnose and could lead to death. Moreover, this condition is often not diagnosed in time to avoid greater consequences. The aim of this study was to identify and describe the occurrence of hyponatremia caused by the interaction of selective serotonin reuptake inhibitors and diuretics. METHODS Prospective observational study. Clinical exams, comparisons of pharmacological profiles of the medications involved, laboratory exams and the application of the Naranjo algorithm were performed for the determination of drug interactions. A review of the literature was also conducted using the International Pharmaceutical Abstracts (PubMed) database. RESULTS Three cases of hyponatremia stemming the interaction of selective serotonin reuptake inhibitors and diuretics were identified and described. The interactions occurred in patients hospitalized for heart treatment (two females and one male). CONCLUSION The occurrence of hyponatremia generally leads to a life-threatening clinical condition that requires a fast diagnosis and efficient intervention. Selective serotonin reuptake inhibitors increase the chances of such an occurrence, especially when used concomitantly with diuretics medications. Physicians should avoid such combinations of medications, if possible, and establish rigorous monitoring with the regular determination of serum sodium. KEYWORDS Drug interaction, hyponatremia, SSRIs, diuretics, adverse drug effect INTRODUCTION Hyponatremia is a significant clinical occurrence that can alter osmolarity, with serious consequences to the general health status of the patient and even the risk of death; indeed, hyponatremia is considered an independent predictor of death [1,2]. This condition has a multifactor etiology, but the most common causes are inappropriate antidiuretic hormone secretion and the depletion of serum sodium due mainly to the use of medications, especially diuretics [3,4,5]. Selective serotonin reuptake inhibitors (SSRIs) constitute another class of medications that are often cited in such cases due to their ability to increase the secretion of vasopressin [6,7,8,9,10]. Symptoms depend on the severity of the reduction in serum sodium below 130 mmol/L, with concentrations less than 120 mmol/L associated with a greater risk of death . Prevention of this clinical situation is of the utmost importance, as treatment, which involves the rapid replacement of serum sodium, constitutes a risk factor for the occurrence of osmotic demyelination . It is recommended that the serum sodium level be increased 10 to 12 mEq/L in a 24-hour period or 18 mEq/L in a 48-hour period [13,4]. Different studies have suggested that the concomitant use of diuretics and SSRIs increases the risk for hyponatremia  due to additive effects of these classes of medication, which can cause inappropriate antidiuretic hormone secretion, leading to a reduction in serum sodium levels due to dilution [16,17,18]. Thus, the aim of the present study was to identify and describe possible real drug interactions between diuretics and antidepressant SSRIs as the cause of hyponatremia. METHODS A prospective observational study was conducted. All patients hospitalized in the cardiology ward of a large hospital in a medium-size capital city in Brazil who took some type of diuretic medication were monitored full time for a period of three months. When patients began the concomitant use of some type of antidepressant SSRI, monitoring was performed with the help of medical assistants and data obtained from the patient charts. Clinical exams, comparisons of pharmacological profiles of the medications involved, laboratory exams and the application of the Naranjo algorithm , were performed for the determination of drug interactions. The Naranjo adverse drug reaction probability scale is a reliable tool for the determination of drug interactions composed of ten topics and respective scores: 1- are there previous studies on this reaction? (yes/+1, no/0, unknown/0); 2- did the adverse reaction occur after the administration of the drug? (yes/+2, no/-1, unknown/0); 3- did the patient improve when the drug was withdrawn or when a specific antagonist was administered? (yes/+1, no/0, unknown/0); 4- did the reaction reappear when the drug was administered? (yes/+2, no/-1, unknown/0); 5- excluding the use of medication, are there other causes capable of determining the emergence of the reaction (yes/-1, no/+2, unknown/0); 6- did the reaction reappear when administering a placebo (yes/-1, no/+1, unknown/0); 7- was the drug detected in the blood or other organic fluids at concentrations considered toxic? (yes/+1, no/0, unknown/0); 8- was the reaction more intense when the dose was increased or less intense when the dose was diminished? (yes/+1, no/0, unknown/0); 9- has the patient previously exhibited the same reaction to the same or similar drug (yes/+1, no/0, unknown/0); and 10- was the adverse reaction confirmed by objective evidence (yes/+1, no/0, unknown/0). The determination of a drug interaction is established using the following score: > 8 points = defined/proven; 5 to 8 points = probable; 1 to 4 points = possible. Factors that could confound the drug interaction as the cause of hyponatremia were investigated and excluded, such as the use of other medications, diseases, kidney function, smoking, increase water intake, vomiting, hyperhidrosis and other less frequent causes. A review of the literature was also conducted using the International Pharmaceutical Abstracts (PubMed) database. This study received approval from the Human Research Ethics Committee of the Federal University of Pernambuco (Brazil) under process number 0069845. RESULTS Among the 73 patients admitted to the cardiology ward for treatment, 24 (32.8%) used some type of diuretic, five of these patients (20.8%) used a concomitant antidepressant SSRI and three (60%) exhibited hyponatremia stemming from a drug interaction between sertraline and spironolactone, sertraline and hydrochlorothiazide or paroxetine and furosemide. Table 1 list the bio-demographic, clinical and pharmacological data of the real drug interactions identified. 1- Drug interactions between diuretics and antidepressant selective serotonin reuptake inhibitors DISCUSSION Although case reports have indicated SSRIs and diuretics separately as capable of producing hyponatremia, this occurrence seems to be more frequent and more significant when these two classes of medications are used concomitantly due to the additive effect on the reduction in serum sodium levels [10-15- 16, 17-20,21]. Indeed, the risk of the occurrence of hyponatremia when an antidepressant SSRI is used concomitantly with a diuretic can be as much as tenfold higher than the use of the antidepressant alone . The majority of studies are in agreement that women and older adults are at greater risk of the occurrence of hyponatremia [10-23,24]. The present study also had a greater number women and older adults. The synergic mechanisms involved in this interaction are likely the increase in the secretion of vasopressin caused by SSRIs, with the consequent reduction in serum sodium due to dilution, and the reduction in sodium following the increase in excretion due to the use of diuretics, during which potassium is also reduced in some situations and vasopressin is further increased . In a controlled retrospective study , evaluated the frequency of severe hyponatremia (considered herein as a sodium concentration less than 125 mmol/L) in hospitalized older adults and found an incidence of 27.55%, with a mortality rate of 27% versus 16.0% in the control (p = 0.057; OR = 1.940). Medications were a significant risk factor after considering confounding factors, such as water intake, tube feeding, vomiting, cirrhosis and hyperhidrosis. The present report is in agreement with available evidence, demonstrating greater risk of the occurrence of a drug interaction leading to hyponatremia when SSRIs are used concomitantly with diuretics, especially in hospitalized patients, older adults and women . The first signs and symptoms appear between 1 and 253 days  and treatment commonly begins after an average of 13 days , which is in agreement with the present findings. The most significant evidence for the confirmation of the interaction was the occurrence of hyponatremia after the initiation of the SSRIs, the improvement of the patient after suspending the antidepressant and the exclusion of other factors. The fact that SSRIs can theoretically diminish the hepatic metabolism of diuretics and even dislocate the diuretic molecules from their bonds to plasmatic proteins may have been an additional factor regarding the interaction outcome. CONCLUSION The drug interaction between diuretics and selective serotonin reuptake inhibitors probably increases the risk of the occurrence of hyponatremia. The present findings serve to warn clinicians, especially psychiatrists and cardiologists, regarding the risks of the concomitant use of medications so that preventive steps can be taken. Moreover, rigorous monitoring should be performed with the regular determination of serum sodium, especially in patients with greater vulnerability. CONFLICT OF INTEREST The authors declare no conflicts of interest associated with this manuscript. REFERENCES Danziger John, Lee Joon, Mark RG, Celi L A, Mukamal KJ. Do Hyponatremia or Its Underlying Mechanisms Associate With Mortality Risk in Observational Data? Crit Care Explor 2020; 2: e0074. Tizoulis P, Bagkeris E, Bouloux PM. A case-control study of hiponatremia as an independent risk factor for inpatient mortality. Clin Endocrinol (Oxf). 2014; 81: 401-407. Correia L, Ferreira R, Correia I, Lebre A, Carda J, Monteiro R, Simão A, Carvalho A, Costa N. Severe hyponatremia in older patients at admission in an internal medicine department. Arch Gerontol Geriatr. 2014; 59: 642-647. Arampatizis S, Gaetcke LM, Funk GC, Schwarz C, Mohaupt M, Zimmermann H, Exadaktylos AK, Lindner G. Diuretic-induced hyponatremia and osteoporotic fractures in patients admitted to the emergency department. Maturitas. 2013; 75: 81-86. Oles KS, Denham JW. Hyponatremia induced by thiazide-like diuretics in the elderly. Outh Med J 1984; 77: 1314-15. Gilboa M, Koren G, Katz R, Melzer-Cohen C, Shalev V, Grossman E. Anxiolytic treatment but not anxiety itself causes hyponatremia among anxious patients. Medicine (Baltimore) 2019; 98: e14334. Fenoglio I, Guy C, Beyens MN, Mounier G, Marsille F, Mismetti P. Therapie. 2011; 66: 139-148. Miler M. Hyponatremia, age-related risk factors and therapy decisions. Geriatrics. 1998; 53: 32-33. Strachan J, Shephero J. Hyponatremia associated with the use of selective serotonin reuptake inhibitors. Aus NZJ Psychiatry. 1998; 32: 295-298. 10- Ten Holt WL, Klaassen CH, Schrijver G. Severe hyponatremia, possibly due to inappropriate antidiuretic hormone secretion, during use of the antidepressant fluoxetine. Ned Tijdschr Geneesked. 1994; 138: 1181-1183. Movig KL, Leufkens HGM, Lenderink AW, et al. Association between antidepressant drug use and hyponatremia: a case-control study. Br J Clin Pharmacol. 2002; 53: 363-9. Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol. 1994; 4: 1522-30. 13- Sood L, Sterns RH, Hix JK, Silver SM, Chen L. Hypertonic saline and desmopressin: a simple strategy for safe correction of severe hyponatremia. Am J Kidney Dis. 2013; 4: 571-8. Assadi F. Hyponatremia: a problem-solving approach to clinical cases. J Nephrol. 2012; 4: 473-80. Diken Aİ, Yalçınkaya A, Erçen Diken Ö, Aksoy E, Doğan İ, Yılmaz S, Çağlı K. Hyponatremia Due to Escitalopram and Thiazide Use After Cardiac Surgery. J Card Surg. 2016;31:96-7. Yoon HJ, Lee KY, Sun IO. Clinical severity of drug-induced hyponatremia: thiazides vs. psychotropics. Clin Nephrol. 2016 ; 85:321-5. Montastruc F, Sommet A, Bondon-Guitton E, Durrieu G, Bui E, Bagheri H, Lapeyre-Mestre M, Schmitt L, Montastruc JL. The importance of drug-drug interactions as a cause of adverse drug reactions: a pharmacovigilance study of serotoninergic reuptake inhibitors in France. Eur J Clin Pharmacol. 2012; 68: 767-75. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother. 2006; 9: 1618-22. Busto U, Naranjo CA, Sellers EM. Comparison of two recently published algorithms for assessing the probability of adverse drug. Br J Clin Pharmacol. 1982;13: 223-7. Rottmann CN. SSRIs and the syndrome of inappropriate antidiuretic hormone secretion. Am J Nurs. 2007; 107: 51-8. Rosner MH. Severe hyponatremia associated with the combined use of thiazide diuretics and selective serotonin reuptake inhibitors. Am J Med Sci. 2004; 327: 109-11. Letmaier M, Painold A, Holl AK, Vergin H, Engel R, Konstantinidis A, Kaspers S, Grohmann R. Hyponatremia during psychopharmacological treatment: results of a drug surveillance programme. Int J Neuropsychopharmacol. 2012; 15: 739-48. Wright SK, Schroeter S. Hyponatremia as a complication of selective serotonin-reuptake inhibitors. Am Acad Nurse Pract. 2008; 20: 47-51. Vu T, Wong R, Hamblin PS, Zajac J, Grossmann M. Patients presenting with severe hypotonic hyponatremia: etiological factors, assessment, and outcomes. Hosp Pract. 1995; 37: 128-36. Kirchner V, Prata LE, Kelly CA. Selective serotonin reuptake inhibitors and hyponatremia: review and proposed mechanisms in the elderly. J Psychopharmacol. 1998; 12: 396-400. 26- Liu BA, Mittmann N, Knowles SR, Shear NH. Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports. Can Med Assoc J. 1996; 155: 519-27.