Severe Hyponatremia Associated with the Combined Use of Thiazide Diuretics and Selective Serotonin Reuptake Inhibitors

doi:10.1097/00000441-200402000-00012

The American Journal of the Medical Sciences

Volume 327, Issue 2, February 2004, Pages 109-111

https://doi.org/10.1097/00000441-200402000-00012 Get rights and content

ABSTRACT

Thiazide diuretics and selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications. Each medication has been associated with the development of severe hyponatremia. The mechanisms involved in the development of hyponatremia differ for each medication. Thiazide diuretics induce hyponatremia by impairment of urinary dilution, renal loss of sodium and potassium, stimulation of antidiuretic hormone (ADH), and perhaps from a dipsogenic effect. SSRIs cause hyponatremia through the syndrome of inappropriate ADH release. Two cases of severe hyponatremia in patients taking both a thiazide diuretic and an SSRI highlight the possibility of a synergistic effect in impairment of renal free water clearance when both medications are given. These two cases serve as a cautionary example and should prompt careful monitoring of patients prescribed both an SSRI and a thiazide diuretic (especially in elderly women, who seem to be at increased risk for this complication).

Section snippets

Case 1

An 84-year-old woman with long-standing hypertension treated with amlodipine 10 mg/day and hydrochlorothiazide 25 mg/day was prescribed paroxetine 20 mg/day for symptomatic depression. Other medications included: 325 mg of aspirin per day and 20 mg of famotidine per day. Laboratory work before the initiation of paroxetine revealed a serum sodium level of 135 mmol/L, potassium of 3.8 mmol/L, and normal renal function. Two weeks later, the patient presented to the emergency room with lethargy, headache,

Discussion

Both thiazide diuretics and SSRIs have been associated with hyponatremia through different but possibly complementary and synergistic mechanisms. Thiazide diuretics, by inhibiting sodium chloride reabsorption in the distal convoluted tubule, impair urinary diluting capacity and lead to modest volume depletion and stimulation of ADH secretion. Because thiazide diuretics act after the ascending limb of the loop of Henle, the hypertonic medullary interstitium is not affected and urinary

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Cited by (57)

Elevated High-Density Lipoprotein Cholesterol Is Associated with Hyponatremia in Hypertensive Patients
2017, American Journal of Medicine
Citation Excerpt :
Based on the analysis models that we performed in the present study, it appears that HDL-C levels are more important than these previously described factors: this is first demonstrated by the fact that HDL-C holds more information content in the GBM predictive model than BMI, age, and sex altogether; second, when lipid levels are not used to build the predictive model, the prediction accuracy decreases significantly, and the BMI takes HDL-C's place as the most informative factor. Several drugs, such as selective serotonin reuptake inhibitors and carbamazepine, are associated with hyponatremia, particularly when they are combined with thiazides.23,24 By performing multivariable logistic models for hyponatremia using drug usage information from the NHANES study, we found significant effects for many of the known drug associations.
Recently, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive lowering of systolic blood pressure is beneficial, but is associated with more adverse events. Hyponatremia was notably more frequent in the intensive treatment group. Investigating its risk factors is crucial for preventing this complication. Our objective in this study was to identify risk factors for hyponatremia in the adult population.
We investigated the baseline demographic, clinical, and laboratory data from the 9361 participants of SPRINT to identify the best predictors of hyponatremia (serum sodium ≤130 mEq/L), and adverse events, which could be attributed to hyponatremia, using machine learning and multivariable Cox proportional hazards models. We confirmed our results in the independent National Health and Nutrition Examination Survey (NHANES) cohort between the years 2005 and 2010 (16,501 participants).
Elevated baseline high-density lipoprotein cholesterol (HDL-C) was a strong predictor of future hyponatremia. Multivariable Cox regression showed hyponatremia events to be significantly increased for SPRINT participants with baseline HDL-C levels in the highest quintile (hazard ratio [HR] 2.8; 95% confidence interval [CI], 2.2-3.7; P <.001), and were also associated with treatment-related serious adverse events (HR 1.6; 95% CI, 1.3-2.1; P <.001). We confirmed the association between HDL-C and hyponatremia in the NHANES cohort (HR 2.5; 95% CI, 1.7-3.7; P <.001).
Elevated HDL-C (≥62 mg/dL) is a risk factor for hyponatremia. Thus, hypertensive patients with elevated HDL-C should be closely monitored for hyponatremia when treated for hypertension.
Severe hyponatremia associated with thiazide diuretic use
2015, Journal of Emergency Medicine
Citation Excerpt :
Hyponatremia can also occur years after taking a thiazide and is likely due to subsequent contributory factors such as a decline in renal function with aging, changes in water or sodium intake, or the ingestion of other drugs that affect free water clearance. Drugs known to increase the likelihood of developing TIH include nonsteroidal antiinflammatory drugs, carbamazepine, and selective serotonin reuptake inhibitors (13–15). Polydipsia caused by psychotropic medications may also predispose to TIH (16).
Thiazide diuretics are commonly used as first-line antihypertensive agents. Hyponatremia is a reported, though uncommon, complication of thiazide use. Although the exact mechanism of thiazide-induced hyponatremia (TIH) is unclear, it can be a significant cause of morbidity and mortality.
We report a 69-year-old man with generalized weakness beginning 2 weeks after starting hydrochlorothiazide (HCTZ). Evaluation revealed a serum sodium level of 120 mmol/L. The patient was admitted and successfully treated with free water restriction and discontinuation of the HCTZ.
Hyponatremia is an uncommon complication of thiazide diuretic use, which frequently presents with nonspecific symptoms. Identification of TIH is crucial to prevent its potentially life-threatening complications.
The syndrome of inappropriate antidiuresis
2012, Revue de Medecine Interne
Le syndrome d’antidiurèse inappropriée (SIAD ; anciennement syndrome de sécrétion inappropriée d’hormone antidiurétique [SIADH]) constitue l’étiologie la plus fréquente de l’hyponatrémie. Il existe une forte association entre mortalité et hyponatrémie qui repose surtout sur la gravité de la maladie sous-jacente. Dans le SIAD, l’hyponatrémie est dite euvolémique mais l’appréciation du volume extracellulaire peut être difficile. La symptomatologie est principalement neurologique pouvant conduire au décès mais des mécanismes d’adaptation permettent de limiter l’œdème cérébral. La notion d’hyponatrémie modérée asymptomatique a été remise en cause sur la constatation d’altérations neurocognitives infracliniques, d’un risque accru de chutes et de fractures. Les étiologies sont classées en six groupes : atteintes cérébrales, infections principalement cérébro-méningées et pulmonaires, médicaments notamment les antidépresseurs, tumeurs, causes génétiques, et idiopathiques. L’hyponatrémie aiguë symptomatique est une urgence thérapeutique non spécifique du SIAD. Lorsque l’hyponatrémie est asymptomatique, la restriction hydrique avec apport de sel est généralement suffisante mais l’urée peut être une alternative. Dans le SIAD chronique, il n’y a actuellement aucune recommandation. La restriction hydrique n’est pas toujours réalisable ; l’urée a démontré son efficacité, sa bonne tolérance et son innocuité au long cours. Les vaptans ont démontré leur bonne tolérance et leur efficacité sur la correction de l’hyponatrémie liée au SIAD dans des sous-groupes d’études, pour des hyponatrémies modérées et des patients asymptomatiques. Dans la seule étude ayant comparé vaptans et urée, l’efficacité et la tolérance sont comparables. Vu la différence de coût entre les vaptans et l’urée et en attendant des études complémentaires, l’urée apparaît actuellement comme le traitement de première intention de l’hyponatrémie du SIAD.
The syndrome of inappropriate antidiuresis (SIAD; formerly the syndrome of inappropriate secretion of antidiuretic hormone) is the most frequent cause of hyponatremia. A strong association exists between mortality and hyponatremia, which reflects the severity of the underlying disease. In SIAD, hyponatremia is associated with normovolaemia but the assessment of extracellular volume can be difficult. Clinical features are mainly neurological and can lead to death but mechanisms of adaptation can limit cerebral oedema. The notion of mild asymptomatic hyponatremia was questioned by the observation of subclinical neurocognitive impairment, a greater risk of falls and fractures. Aetiologies are classified into six groups: neurologic disorders, infections mainly cerebral, meningeal and pulmonary, drugs in particular antidepressants, tumors, genetic causes, and idiopathic. Symptomatic acute hyponatremia is a therapeutic emergency that is not specific of SIAD. When hyponatremia is asymptomatic, fluid restriction with salt intake is generally sufficient but urea can be an alternative. In chronic SIAD, there is currently no recommendation. Fluid restriction is not always feasible; urea has proved its efficacy, its good tolerance and its long-term harmlessness. Vaptans have demonstrated their good tolerance and their efficacy on the correction of hyponatremia from SIAD in studies subgroups, for moderate hyponatremia and asymptomatic patients. In the only study having compared vaptans and urea, efficacy and tolerance were similar. Because of the cost difference between vaptans and urea and while waiting for follow-up studies, urea appears at present as the first-line treatment of hyponatremia in SIAD.
Diuretic-associated hyponatremia
2011, Seminars in Nephrology
Citation Excerpt :
Chow et al76 did not find a correlation between thiazide dose factored for body weight and the incidence of hyponatremia. Concomitant use of thiazides with other agents that cause hyponatremia, such as selective serotonin reuptake inhibitors or seizure medication, may predispose to hyponatremia but often are difficult to avoid.82,83 Hyponatremia in the setting of psychosis and associated polydipsia has been well described, and development of severe hyponatremia may occur when a thiazide is added to the regimen of patients with psychogenic polydipsia and mild hyponatremia.18,84,85
Soon after their introduction in 1957, thiazide diuretics became a recognized cause of hyponatremia. Thiazides may be the sole cause and they may exacerbate hyponatremia in patients with disorders that cause the syndrome of inappropriate antidiuretic hormone secretion. Although thiazides do not inhibit the ability to concentrate the urine, they impair diluting ability in several ways: inhibition of sodium and chloride transport at cortical diluting sites; stimulation of vasopressin release; reduction of glomerular filtration and enhanced proximal water reabsorption, which reduce delivery to the distal diluting sites; and, possibly, a direct effect on water flow in the collecting duct. Water retention caused by impaired water excretion combined with cation depletion may result in severe hyponatremia. Thiazides should be avoided in frail elderly patients with chronically high water intake or in others who depend on the excretion of maximally dilute urine to maintain fluid balance, such as patients with psychogenic polydipsia or heavy beer drinking. Inadvertent rapid correction of hyponatremia is common in thiazide-induced hyponatremia because the ability to dilute the urine is restored when the diuretic is discontinued and volume deficits are repaired. Hypokalemia, which often is present, increases the susceptibility to osmotic demyelination syndrome and replacement of potassium deficits contributes to the increase in serum sodium concentration.
Hyponatraemia during psychopharmacological treatment: Results of a drug surveillance programme
2012, International Journal of Neuropsychopharmacology
Behavior drugs
2024, Pharmacology in Veterinary Anesthesia and Analgesia

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Case ReportsSevere Hyponatremia Associated with the Combined Use of Thiazide Diuretics and Selective Serotonin Reuptake Inhibitors

ABSTRACT

Section snippets

Case 1

Discussion

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitors or calcium channel blocker vs. diuretic. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT)

JAMA

Diuretic-induced hyponatremia

Ann Intern Med

Severe diuretic-induced hyponatremia in the elderly. A series of eight patients

Arch Intern Med

Hypoosmolal states—Hyponatremia

Case Reports
Severe Hyponatremia Associated with the Combined Use of Thiazide Diuretics and Selective Serotonin Reuptake Inhibitors