NSAIDs: Electrolyte complications

INTRODUCTION — Nonsteroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed analgesics worldwide. These agents reduce pain, inflammation, and fever by inhibiting cyclooxygenase (COX), which results in decreased synthesis of prostaglandins. COX has two isoforms; inhibition of COX-1 is responsible for the gastrointestinal side effects of NSAIDs, while their desired antiinflammatory effects are due to inhibition of COX-2 [1]. The COX-2 isoform is constitutively present in the kidney, and, therefore, both nonselective NSAIDs and more selective COX-2 inhibitors reduce renal prostaglandins. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action".)

Renal vasodilatory prostaglandins promote the secretion of renin, impair sodium reabsorption in the loop of Henle and cortical collecting tubule, and partially antagonize the ability of antidiuretic hormone (ADH) to increase water reabsorption in the collecting tubules [2-5]. Locally generated prostaglandins also may mediate part of the natriuretic effect of dopamine and of natriuretic peptides [6,7].

These actions are not of major importance in normal subjects in whom basal renal prostaglandin production is relatively low. However, they may become clinically significant when prostaglandin synthesis is stimulated by underlying kidney disease or by the vasoconstrictors angiotensin II or norepinephrine. Secretion of these vasoconstrictors is increased in states of effective volume depletion: true volume depletion due to gastrointestinal or renal losses (as with diuretic therapy) or reduced tissue perfusion due to heart failure or cirrhosis.

In the setting of effective volume depletion, NSAIDs, which inhibit prostaglandin synthesis, can produce a variety of complications related to kidney dysfunction, each of which is reversible with discontinuation of therapy [2,3]. These include hyperkalemia, hyponatremia, and edema. These complications are mediated in part by reductions in the secretion of renin and aldosterone and by increased activity of ADH [2,3,8].

In addition, vasoconstriction due to decreased synthesis of vasodilator prostaglandins can impair kidney function and exacerbate underlying hypertension and heart failure. These issues are discussed separately:

●(See "NSAIDs: Acute kidney injury".)

●(See "NSAIDs and acetaminophen: Effects on blood pressure and hypertension".)

●(See "NSAIDs: Adverse cardiovascular effects".)

ELECTROLYTE COMPLICATIONS

Hyperkalemia — NSAIDs have two effects that can promote the development of hyperkalemia: They lower renin secretion by the kidney, which is normally mediated, in part, by locally produced prostaglandins [2,3,9], and they impair angiotensin II-induced aldosterone release [9]. The ensuing fall in aldosterone secretion will reduce urinary potassium excretion, which will tend to raise the plasma potassium concentration.

The magnitude of the effect of NSAIDs on the plasma potassium concentration was illustrated in a study of 50 hospitalized patients in whom indomethacin therapy was initiated [10]. The plasma potassium rose by less than 0.5 mEq/L in 40 percent, 0.5 to 0.9 mEq/L in 34 percent, and by 1 mEq/L or more in 26 percent; these changes began within the first few days of therapy. One would expect smaller elevations in plasma potassium in healthy individuals. On the other hand, the hyperkalemic effect may be more pronounced in two settings: if there is an NSAID-induced reduction in glomerular filtration rate, which can lead to reduced sodium and water delivery to the potassium secretory site in the collecting tubules, or if there is concurrent use of other drugs that raise the plasma potassium such as angiotensin inhibitors and potassium-sparing diuretics [3]. (See "NSAIDs: Acute kidney injury", section on 'Mechanism of acute kidney injury'.)

In the absence of other risk factors, NSAIDs are unlikely to produce moderate to severe hyperkalemia. In an observational study of 1,267,025 new NSAID users, for example, NSAID use alone was not associated with the development of hyperkalemia (defined as a serum potassium ≥6 mEq/L) [11]. However, the risk for this degree of hyperkalemia was increased when NSAIDs were combined with an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), or with radiocontrast media exposure. In another large study that examined new use of NSAIDs among older adults, moderate hyperkalemia (≥5.5 mEq/L) was twice as common in the first month of NSAID use (0.40 versus 0.27 percent among non-users), although rates of more severe hyperkalemia (≥6.0 or ≥6.5 mEq/L) were similar [12]. Baseline serum potassium, estimated glomerular filtration rate (eGFR), ACE inhibitor or ARB use, diuretic use, and NSAID dose did not significantly modify the association between NSAID use and hyperkalemia.

Hyponatremia — NSAIDs diminish the normal inhibitory effect of prostaglandins on the activity of antidiuretic hormone (ADH) and can therefore reduce free water excretion [4,13]. In conditions associated with high and relatively nonsuppressible levels of ADH, such as the syndrome of inappropriate ADH secretion or effective volume depletion, as in patients with severe heart failure, NSAID-induced water retention can induce or worsen hyponatremia [2,14]. NSAIDs may also increase the susceptibility of older adults to thiazide diuretic-induced hyponatremia [15]. (See "Hyponatremia in patients with heart failure" and "Diuretic-induced hyponatremia".)

Edema — Removal of the inhibitory effect of prostaglandins on sodium reabsorption with both nonselective and cyclooxygenase (COX)-selective NSAIDs can lead to sodium retention. With prolonged therapy, healthy individuals may have a weight gain of as much as 0.5 to 1 kg, while the degree of sodium and water retention may be more prominent in patients with underlying heart failure or cirrhosis [3,16]. The increase in sodium reabsorption contributes to the relative resistance to diuretics associated with NSAID therapy [3,17]. NSAIDs may also exacerbate heart failure, an effect that is probably due more to increased afterload resulting from NSAID-induced systemic vasoconstriction than to sodium retention. (See "NSAIDs: Adverse cardiovascular effects".)

Hypokalemia and renal tubular acidosis — Several patients with ibuprofen-induced renal tubular acidosis (RTA) associated with profound hypokalemia (serum potassium as low as 1 mmol/L) have been reported [18-24]. The first cases were identified in Australia, where ibuprofen-codeine combination products are available over the counter, and most, but not all, were taking excessive doses of ibuprofen [18,19]. However, subsequent reports have revealed that this NSAID complication is not limited to concurrent codeine use or to toxic doses of ibuprofen [20-24].

As of July 2022, there were 41 published reports describing 50 cases (26 males and 24 females; 36 adults and 14 children) with often profound hypokalemia, acidosis, or both after ingestion of ibuprofen; 88 percent of the patients were taking an excessive dose (more than 40 mg/kg body weight daily), but 12 percent were taking normal doses [24]. Approximately half of these cases occurred after a single large dose (96 to >1000 mg/kg) and approximately half after nontoxic doses taken for a longer period (from two weeks to over a year).

Most acute ibuprofen overdoses produced an elevated anion gap, often with documented lactic acidosis and normal or elevated serum potassium. By contrast, the more chronic cases presented with hypokalemia, a hyperchloremic metabolic acidosis, a urine pH >5.5, and a low urine anion gap consistent with a diagnosis of RTA. Urinary potassium wasting was documented in all cases and was not explained by diuretic use or magnesium deficiency. Renal glycosuria was not observed. In most patients, discontinuation of ibuprofen resulted in complete biochemical resolution within days. The mechanism by which ibuprofen induces RTA is unknown.

Hypokalemia has been reported in one patient taking naproxen, which, like ibuprofen, is a propionic acid derivative, but it has not been associated with other classes of NSAIDs.

CHOICE OF NSAID — The above complications can generally be induced by any of the NSAIDs, although indomethacin may be the most potent. In comparison, renal prostaglandin synthesis may be relatively spared following therapy with sulindac or low-dose aspirin [3,25]. With aspirin, for example, the inhibition of glomerular cyclooxygenase (COX) may only be partial and transient, in contrast to the irreversible acetylation in platelets [25]. The possible mechanisms by which sulindac might, in some patients, spare renal prostaglandin synthesis are discussed separately. (See "NSAIDs: Acute kidney injury", section on 'Mechanism of acute kidney injury'.)

SUMMARY

●Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit prostaglandin synthesis. In the setting of effective volume depletion, this inhibition can cause hyperkalemia, hyponatremia, and edema. (See 'Introduction' above.)

●NSAIDs cause hyperkalemia by decreasing renin secretion and impairing angiotensin II-induced aldosterone release. The ensuing fall in aldosterone secretion reduces urinary potassium excretion, which raises the plasma potassium concentration. (See 'Hyperkalemia' above.)

●NSAIDs diminish the inhibitory effect of prostaglandins on the activity of antidiuretic hormone (ADH); the ensuing increase in ADH activity can reduce free water excretion, which can lead to water retention and induction or exacerbation of hyponatremia in conditions associated with high and nonsuppressible levels of ADH, such as the syndrome of inappropriate ADH secretion or effective volume depletion, as in patients with severe heart failure or cirrhosis. NSAIDs may also increase the susceptibility of older adult subjects to thiazide diuretic-induced hyponatremia. (See 'Hyponatremia' above.)

●NSAIDs can cause sodium retention that is typically mild in healthy individuals but can lead to exacerbation of edema and contribute to diuretic resistance in patients with underlying heart failure or cirrhosis. (See 'Edema' above.)

●Rarely, NSAIDs may produce hypokalemia and metabolic acidosis. (See 'Hypokalemia and renal tubular acidosis' above.)

●The above complications can generally be induced by any of the NSAIDs, although indomethacin may be the most potent and sulindac or low-dose aspirin the least potent. (See 'Choice of NSAID' above.)