Ibuprofen is a non-steroidal anti-inflammatory drug that is used to relieve pain. Its mechanism of action involves inhibiting COX-1/2, thus reducing the production of prostaglandins which play a role in pain and inflammation (FitzGerald and Patrono, 2001). COX-1 is involved in regulating renal haemodynamics and GFR, while COX-2 is responsible for regulating salt and water excretion.

Hyponatremia is a condition where the concentration of sodium in the blood falls below 135mEq/L (Ayus et al., 2012) (FitzGerald and Patrono, 2001). Sodium is a cation that is found in the extracellular fluid (ECF) of the body and is regulated by the Na+/K+ ATPase pump. It is important for maintaining fluid balance, isotonicity, acid-base balance, nerve conduction, and blood osmolarity (see figure 1). Vasopressin (ADH) is a hormone that regulates the reabsorption of water in the kidneys by stimulating aquaporin, which allows water to move from the interstitial fluids to the tubules. This is positively feedbacked by protein Kinase A, allowing for further ADH entry (Widmaier et al., 2016). The bulk of sodium reabsorption occurs in the proximal convoluted tubule, while reabsorption based on the RAAS system occurs in the distal tubule, where aldosterone inhibits sodium excretion (Watson and Austin, 2021). Maintaining sodium balance is critical for maintaining biological processes and homeostasis.

Both drugs and diseases can lead to hyponatremia. Drugs can cause a condition called syndrome of inappropriate secretion of antidiuretic hormone (SIADH), where vasopressin increases due to decreasing osmotic pressure and increased dilution of blood volume in the ECF, leading to hypotonic hyponatremia (Medicines Complete, 2023). This can constrict blood vessels, leading to an increase in GFR. Chronic kidney disease can also cause fluid overload, leading to an inability of the kidneys to filter or reabsorb water and sodium (Lim et al., 2016).

Symptoms of hyponatremia are usually unspecific and related to changes in body fluid osmolarity, with adverse effects predominantly associated with the neuromuscular system (see figure 2). In rare cases, seizures may occur due to cerebral oedema caused by water moving into the brain cells due to an increasing concentration in the ECF, creating a concentration gradient that makes neuronal movement difficult and may lead to death (Ayus et al., 2012). Respiratory symptoms can also occur, leading to pulmonary oedema and respiratory arrest in severe cases (Moritz and Ayus, 2003).

In healthy populations, prostaglandins do not have a significant effect on renal functionality. However, patients with SIADH or diseases are at greater risk of developing ibuprofen-induced hyponatremia (Liamis, Milionis and Elisaf, 2008). This is because ibuprofen removes the inhibitory effect of renal prostaglandin on ADH release, increasing sodium retention and ADH concentration, and diluting sodium concentrations in the blood (Baker and Perazella, 2020) (see figure 4). However, this is a rare occurrence, as prostaglandins may also directly suppress central ADH secretion, which is why healthy individuals are less affected.

Numerous case studies indicate a relationship between ibuprofen use and hyponatremia. One such case study focused on a 76-year-old Caucasian male who took 400mg of ibuprofen for a month and developed SIADH (syndrome of inappropriate antidiuretic hormone secretion), resulting in hyponatremia with a decrease in blood sodium levels to 116mmol/L. Other potential causes, such as malignancies, were ruled out by imaging tests. Once the patient was treated with tolvaptan for the decline in sodium levels, his condition stabilized, and there was a significant improvement in sodium levels, as illustrated in figure 5. Tolvaptan reduces the binding of ADH to V2 receptors on distal convoluted tubules, allowing free water removal without sodium loss, resulting in hypervolemic-type hyponatremia accumulation, which could be a treatment for hyponatremia-induced SIADH (Artom et al., 2013).

Another study, conducted by Blum, analysed a 55-year-old woman with advanced chronic renal failure who used 400mg of ibuprofen for three days. There was a notable increase in her sodium levels when she discontinued the drug, as shown in figure 6 (Blum and Aviram, 1980).

Due to the limitations of case studies, such as a lack of external validity, meaning results cannot always be generalised to larger populations, and comorbidities, findings of the two studies should be interpreted with caution. Also, the first study analysed an elderly patient who had an increased risk of hyponatremia due to polypharmacy where multiple drugs could cause an electrolyte imbalance and decreased kidney ability. Moreover, the studies were conducted over a short duration, making it challenging to evaluate the long-term effects, thus decreasing the findings' reliability. However, the studies' ecological validity is promising since they represent real-life cases.

Overall, most research suggests that hyponatremia-induced by ibuprofen is a rare occurrence, and further research is required within larger population groups and over a more extended duration to perceive the correlation between ibuprofen and sodium.

The references cited within this review are based on reliable peer-reviewed literature, journals, and national guidelines and suggest evidence for ibuprofen-induced hyponatremia. Furthermore, there is no evidence to support that ibuprofen leads to hypernatremia.

References

Artom, N. et al. (2013) Syndrome of Inappropriate Antidiuretic Hormone Secretion and Ibuprofen, a Rare Association to Be Considered: Role of Tolvaptan, Case Reports in Endocrinology. Available at: https://doi.org/10.1155/2013/818259.

Ayus, J.C. et al. (2012) Is chronic hyponatremia a novel risk factor for hip fracture in the elderly?, Nephrology Dialysis Transplantation, 27(10), pp. 3725–3731. Available at: https://doi.org/10.1093/ndt/gfs412.

Baker, M.K. and Perazella, M.A. (2020) NSAIDs in CKD: Are They Safe?, American Journal of Kidney Diseases, 76(4), pp. 546–557. Available at: https://doi.org/10.1053/j.ajkd.2020.03.023.#

Blum, M. and Aviram, A. (1980) Ibuprofen induced hyponatraemia, Rheumatology, 19(4), pp. 258–259. Available at: https://doi.org/10.1093/rheumatology/19.4.258.

EUFIC (2021). Sodium: foods, functions, how much do you need & more. [online] www.eufic.org. Available at: https://www.eufic.org/en/vitamins-and-minerals/article/sodium-foods-functions-how-much-do-you-need-more [Accessed 16 Mar. 2023].

In the field of medicine, it is important to understand the pathophysiology of drug-induced hyponatremia. Kim (2022) provides in-depth insights into this topic in the Journal of Clinical Medicine. By analyzing the impact of various pharmaceuticals, Kim offers valuable information that can help healthcare professionals prevent or manage this condition.

Liamis, Milionis, and Elisaf (2008) also address the issue of drug-induced hyponatremia in a review article. Their work can be found on ClinicalKey and offers a comprehensive overview of the causes and effects of hyponatremia. This article, along with Kim's, highlight the importance of recognizing the risks associated with different medications.

Furthermore, Lim et al. (2016) provide evidence linking hyponatremia to fluid imbalances and adverse renal outcomes in patients with chronic kidney disease who are administered diuretics. Their research highlights the importance of monitoring fluid balance in patients taking diuretics to prevent hyponatremia.

MedicinesComplete (2023) is an online resource that provides comprehensive information on hyponatremia, including its causes and how it relates to Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH). This resource is a valuable tool for healthcare professionals looking to deepen their understanding of hyponatremia.

In addition, Moritz and Ayus (2003) examine the pathophysiology and treatment of hyponatremic encephalopathy in their article. They offer updated insights into managing this condition and preventing serious complications.

Vandergheynst et al. (2016) focus on the neurological impact of hyponatremia. Their research suggests that this condition can cause nerve conduction and muscle weakness, among other issues. This emphasizes the importance of monitoring hyponatremia and addressing it promptly to prevent further complications.

Finally, Watson and Austin (2021) provide a comprehensive overview of human fluid balance in the context of physiology. Their analysis offers insights into the mechanisms involved in regulating fluid balance and how this can be impacted by various factors, including medications.

Overall, these resources offer a comprehensive understanding of drug-induced hyponatremia and highlight the importance of recognizing the risks associated with different medications to prevent serious complications. Understanding the pathophysiology of hyponatremia can help healthcare professionals provide better care for their patients and promote better outcomes.