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 [11].

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 [12]. 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 [15] 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 [19], 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 [22].

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 [19]. In a controlled retrospective study [3], 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 [4]. The first signs and symptoms appear between 1 and 253 days [25] and treatment commonly begins after an average of 13 days [26], 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.

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Diagnóstico, Evidências e Rigor Diagnóstico em Psiquiatria

Em função da extensa variedade humana e da circunstância do momento clínico, o entendimento sobre a melhor prática clínica, é de que ela deva ser baseada na relação direta de evidências científicas consolidadas em sua temporalidade e, conhecimento clínico com sustentação em estudos cientificamente bem orientados.

É provável que a medicina no geral, nunca possa ser exercida baseada absolutamente em evidências. Além da questão das variações em si, o momento clínico e a evolução das doenças, estão submetidos a um número muito grande de variáveis. Talvez seja certo dizer, que nunca trataremos completamente uma mesma doença da mesma maneira duas vezes por todo o seu ciclo.

Entendo como evidência científica, um conjunto de dados objetivos, decorrente de estudos que utilizam o método e a análise matemática adequada à hipótese proposta, e que corresponde aos fatos. Deve se submeter a refutações vigorosas, uma única refutação cientificamente bem orientada, é suficiente para que a teoria seja refeita. No caso de sobreviver as refutações, adquire um maior grau de validade e poder de generalização.

Em psiquiatria a situação é mais complexa, porque exige para além do ato médico padrão cientificamente orientado, a capacidade do psiquiatra para lidar com a subjetividade. Assim como a mente é a resultante da fantástica interação do cérebro com o ambiente, a subjetividade é a resultante da capacidade do indivíduo em significar e ressignificar as coisas, no processo de formação dos vários níveis de diversidade do sujeito.

A boa notícia é que diferentemente do que Sartre pensou, o homem como um eterno vir a ser:

"ele é o que não é e não é o que é, porque sempre poderá fazer uma escolha diferente"

O homem é em si, ele mesmo; apesar de ter a possibilidade quase infinita de escolher algo que o torne diferente, essa diferença que ele possa ser nunca é suficiente para torná-lo diferente de si. Desse modo, podemos dizer que o homem é o único ser em que o mesmo é diferente.

Ao final, podemos afirmar categoricamente que, apesar de todas as possibilidades e variações, o homem não consegue se libertar do que é. Ele muda de comportamento, mas não muda o que ele é.

Desse modo, hoje temos uma neurobiologia bastante avançada das doenças mentais e de alguns transtornos de personalidade, que associada ao rigor da anamnese que considera a tridimensionalidade semiológica em psiquiatria: sinais e sintomas mentais, comportamentais e físicos, têm condições de ter um maior rigor diagnóstico, com mais afirmação categórica de sua validade e ser cientificamente bem orientado. Agora podemos entender a doença na sua dimensão neurobiológica e a pessoa humana na sua dimensão existencial. Essa orientação científica nos permite livrar o paciente da dubiedade diagnóstica e principalmente, dos desvios das condutas farmacocêntricas radicais ou das intervenções psicocêntricas fanáticas.

Douglas Dogol Sucar.

Psicoterapias pertencem a Alguém?

Crie um subtítulo para o post no blog que resuma numa frase curta e atraente o seu post. Assim seus leitores vão querer continuar a ler.

Quando fiquei sabendo da notícia que um grupo de psicólogos havia, junto ao Senado Federal, entrado com uma Sugestão 40/2019, no sentido de tornar exclusividade a prática de psicoterapia por psicólogos com CRP ativo, fui tomado por um sentimento de surpresa e de indignação! Após um certo tempo de “decantação”, foi me ocorrendo o questionamento do porquê agora estaria ocorrendo isto?

Sou médico psiquiatra, psicanalista, professor de psiquiatria FAMED/UFRGS, agora aposentado, há quase 50 anos e jamais havia me defrontado com situação semelhante! Fui professor de psiquiatria com ênfase em Psiquiatria Psicodinâmica, em especial em Psicoterapia de Orientação Analítica, para muitas gerações de Psiquiatras e, no Curso de Especialização em Psicoterapia de Orientação Analítica, para inúmeros psicólogos igualmente.

Minha formação foi certamente influenciada pelas teorias freudianas e de seus seguidores, grande parte deles com diferentes formações profissionais o que só vieram a contribuir para a expansão do pensar psicanalítico. Acompanhei durante estes anos a evolução da técnica e da teoria psicanalítica, da psicoterapia e da evolução da psiquiatria, da neuropsiquiatria e da psicofarmacologia.

Quem era Freud? Médico vienense, neurologista, gênio, foi a Paris aprender com Charcot sobre as paralisias histéricas, denominação da época, e descobriu a importância dos conflitos inconscientes na gênese dos sintomas de onde deduziu a formação de uma teoria psicológica: a psicanálise! A partir de então começou a divulgar esta teoria acreditando ser uma forma de tratar determinadas alterações emocionais, de maneira indiscriminada, inclusive para leigos.

Desta vertente se originaram várias outras formas de psicoterapias, como a Psicoterapia de Grupo, Psicoterapia Cognitivo Comportamental e Interpessoal, referindo as mais comuns em nosso meio e com tradição científica de resultados, todas no sentido de se adaptarem a cada caso ou situação específica.

Infelizmente nossos governantes com o objetivo de baratearem a assistência a saúde, optaram pela abertura indiscriminada de cursos de graduação na área da Psicologia e agora na área Médica, sem o devido cuidado da necessidade e da qualidade dos referidos cursos, não havendo o necessário cuidado de um exercício digno das profissões. O que vemos é uma luta por mercado de trabalho cada vez maior com influência na desvalorização para esta assistência.

O valor de uma consulta psiquiátrica em planos de saúde é maior que o valor de um atendimento em psicoterapia por um psicólogo. Acredito, sob meu ponto de vista, ser esta a causa maior da Sugestão 40/2019, a reserva de mercado!

Assim como compete ao psiquiatra, além da psicoterapia, também a prescrição de medicamentos por sua formação médica, determinadas tarefas por sua especificidade de formação, compete também ao psicólogo, como testagens e avaliações profissionais entre outras tantas. Ao contrário isto não nos afasta, mas nos aproxima em termos de complementação de conhecimentos e melhores condições de um atendimento integral.

Acredito que, quando a competividade se basear em normas e leis ao invés de competência, atualização e conhecimento, estaremos empobrecendo nossa capacitação e na verdade quem perderá nisto tudo, além de nós mesmos, será o objetivo de nossas vidas profissionais, isto é, a pessoa que está em sofrimento mental!

Fernando Grilo Gomes

(Coordenador do Departamento de Psicoterapias)

Douglas Dogol Sucar (Presidente da Associação Brasileira de Neuropsiquiatria)