Pain-free today, weak tomorrow: a case of electrolyte disorder due to diclofenac misuse

Abstract

Background

The nephrotoxic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are widely acknowledged. In particular, diclofenac is the most commonly prescribed NSAIDs, but no previous findings of electrolyte disturbances were reported following its administration.

Case report

We presented the case of a man who experienced significant weakness associated with severe deficiencies in potassium, calcium, and magnesium after misusing diclofenac because of severe back pain.

Conclusions

This case emphasizes the need of awareness about the electrolyte imbalances and electrolyte disturbances associated with the misuse of diclofenac, which is a widely available drug. This is a case report which does not need a Clinical Trial Number.

Background

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed medications in pain management; they act through the inhibition of cyclooxygenases, thus reducing the production of many different prostaglandins which are involved in multiple physiopathological pathways.

The pleiotropic action of prostaglandins explains both the analgesic and anti-inflammatory action and the adverse effects such as the impairment of kidney and platelet function with an increasing risk of renal injury and bleeding; moreover, NSAIDs can also cause gastric and duodenum ulcers by reducing the secretion of protective mucus [1]. Here we reported for the first time in the literature a case of hypokalemia, hypocalcemia, and hypomagnesemia related to the misuse of diclofenac, which is one of the most commonly used NSAIDs [2].

Case presentation

A 73-year-old man presented to our clinic complaining of back pain for approximately three days, for which he took a diclofenac 75 mg intramuscular injection, yielding no relief. Due to the ongoing painful symptoms, he received two additional diclofenac intramuscular injections on the same day. He noted that four hours after the last diclofenac injection, he started experiencing nausea and dizziness, followed by acute muscle paralysis in both lower extremities. He denied any other medication; in particular, he did not take diuretics; he denied any variations in his diet during those painful days and he did not suffer from any kind of eating disorder. He was affected by hypertension treated with amlodipine. He exhibited previous biochemical exams, which were normal. There was no history of diarrhea or vomiting and family history was unremarkable; he was recently diagnosed with spondylarthrosis without signs of compression and no neurological deficits were found. Furthermore, electromyographic study and abdominal ultrasound showed no pathological findings. Arterial blood pressure was 110/60 mmHg and electrocardiogram showed no relevant alterations. He did not present symptoms or sign of infections. Blood tests at the time of symptoms showed hypokalaemia (serum potassium 2.6 mmol/L), hypocalcaemia (serum calcium 6.2 mg/dl), hypomagnesemia (serum magnesium 0.5 mg/dl) with a normal renal function. Urinary pH was 6.5. The arterial blood gas analysis revealed a metabolic hyperchloremic acidosis with normal anion gap. Thyroid function and autoimmune tests were in normal ranges. Supine plasma renin activity was 1.5 microU/ml, and plasma aldosterone concentration was normal.

The patient refused hospitalization and intravenous treatment, so he was treated as an outpatient clinic patient. He was treated with 600 mg orally potassium chloride tid. Subsequently, his serum potassium levels exhibited a gradual increase, reaching 3.2 mmol/L in the following days. Concurrent hypomagnesemia was corrected with magnesium supplementation with a daily dosage of 1,500 mg, resulting in an improvement of magnesium levels. Additionally, calcium supplementation was instituted with calcium carbonate at a dosage of 1000 mg tid, along with calcitriol administered at 0.5 micrograms tid. This intervention led to an elevation in serum calcium levels, reaching up to 8 mg/dl.

At the subsequent visit, on day 15 following the start of the therapy, laboratory assessments revealed potassium levels of 4 mmol/L, calcium levels of 10 mg/dL, and magnesium levels of 1.6 mg/dL (Table 1). After a month, all values of the above-mentioned electrolytes normalized, and the previously reported weakness resolved.

Table 1 Laboratory investigations

Discussion and conclusions

We presented the first case of electrolytes disturbances caused by diclofenac misuse. The nephrotoxic effects of NSAIDs, including acute and chronic kidney injury, interstitial nephritis and nephrotic syndrome, are widely acknowledged. In particular, the effect on tubular function of propionic acid derivatives, as ibuprofen and naproxen, was formerly reported in literature with biochemical alterations similar to our case report, but no previous findings of electrolyte disturbances were reported following the administration of an acetic acid derivative such as diclofenac [3].

Renal prostaglandin (PG) production, especially through cyclooxygenase-1 (COX-1) and possibly cyclooxygenase-2 (COX-2), is essential for maintaining kidney function in situations where renal blood flow is reduced. Local blood vessels, salt, and water balance are actively regulated by PGs, which have an impact on kidney function. In addition to maintaining kidney blood flow, renal PGs have an impact on renin secretion, reduce sodium reabsorption in specific tubules, and partially reverse the effects of antidiuretic hormone on water reabsorption. The use of NSAIDs inhibiting cyclooxygenase in low-fluid conditions disrupts the vasodilator effects of PGs. Additionally, PGE2 produced in the kidney inhibits cyclic adenosine monophosphate (cAMP) levels, which tonically influences the expression of the Na-K-2Cl cotransporter in the thick ascending limb [4].

One of the most widespread members of this class of molecules is diclofenac, which is currently used for the treatment of pain and inflammation associated with conditions such as arthritis and musculoskeletal disorders [2, 5]. Diclofenac inhibits COX-1 and COX-2, which synthetize PGs from arachidonic acid. The renal physiology is partly dependent on COX-mediated pathways; in fact, COX-1 and COX-2 are constitutively expressed in the kidney, which could be consequently affected by the action of NSAIDs [6].

Diclofenac, akin to other NSAIDs, has the potential to elicit renal side effects through the inhibition of prostaglandin synthesis. Presently, there exists no specific agent designed to mitigate nephrotoxicity induced by diclofenac sodium [7].

According to reported studies, the side effects of using diclofenac, especially when combined with other drugs or when there are comorbidities, include acute kidney damage and reduced renal function [8]. Our patient did not have a pre-existing kidney disorder but was documented with hypertension. However, being part of the geriatric demographic, the patient exhibited heightened susceptibility to nephrotoxic drugs, attributable to the natural aging process affecting renal function.

The treatment of electrolyte disorders does not follow guidelines and has no consensus as to the pathogenic mechanism involved. In general, a broad group of drugs were used in this case to rebalance the biochemical and clinical situation. In particular, potassium and magnesium supplementation and calcium regulation restored the patient’s physiological situation. Muscle paralysis achieved immediate improvement after correction of plasma potassium with oral potassium chloride and plasma calcium with calcium carbonate.

In contrast to findings documented in the literature for other NSAIDs, the presented case exhibited no discernible alteration in renal function, as evidenced by the absence of changes in creatinine indices or a reduction in diuresis.

In fact, of particular interest in our patient was the profound hypokalemia, hypomagnesemia and hypokalemia with normal renal function which, to the best of our knowledge, have not been previously reported with a misuse of diclofenac. We excluded the use of proton pump inhibitors or drugs interfering with magnesium absorption or elimination or a reduced intake. Indeed, the patient followed a mediterranean diet. The precise mechanism by which the administration of diclofenac in our patient led to the cumulative electrolyte damage remains unclear [9]. We hypothesized that multiple mechanisms can act in the development of these disturbances: firstly, the possible inhibition of carbonic anhydrase II existing in both distal and proximal renal tubules, leading to the lack of bicarbonate ions reabsorption, as already described for ibuprofen. Therefore, the metabolic acidosis is triggered and sodium reabsorption is also impaired, leading to increased sodium delivery in the distal tubule, and increased excretion of potassium by the kidneys [7]. Secondly, diclofenac could act as a strong inducer of oxidative stress [10]. Thirdly, in vivo studies clearly showed that the use of diclofenac can affect mitochondria metabolism [11].

In conclusion, this case underscores the imperative of acknowledging this potential risk and the potential for life-threatening, albeit reversible, electrolyte and acid-base disturbances that may arise with the widespread availability of these specific types of NSAIDs.