Diuretic-Related Side Effects: Development and Treatment

Domenic A. Sica, MD

In This Article


Both thiazide and loop diuretics increase urinary Mg2+ excretion. All K+-sparing diuretics diminish the magnesuria that accompanies thiazide or loop diuretic use.[33]Prolonged therapy with thiazide and loop diuretics, on average, reduces plasma Mg2+ concentration by 5%-10%, although patients can develop more severe hypomagnesemia in association with similarly-sized total body deficits.[34] Cellular Mg2+ depletion occurs in up to 50% of patients receiving thiazide diuretics and can be present despite normal serum Mg2+ concentrations. Hypomagnesemia occurs more frequently in the elderly, and in those receiving high-dose loop diuretic therapy for extended periods of time (such as heart failure patients).[35] Hypomagnesemia often coexists with hyponatremia and hypokalemia, with one study finding 41% of patients with hypokalemia to also have low serum Mg2+ concentrations.[36] Hypocalcemia and/or hypokalemia found in association with low serum Mg2+ concentrations can prove refractory to all treatment measures until the underlying Mg2+ deficit is corrected.[37]

The measurement of serum Mg2+ concentration continues as the everyday test for uncovering hypomagnesemia[38,39] ; however, the presence of hypomagnesemia can be suspected from characteristic ECG, neurologic and/or neuromuscular findings. On ECG, hypomagnesemia can present as prolongation of the Q-T and P-R intervals, widening of the QRS complex, ST segment depression, and low T waves, as well as supraventricular and ventricular tachyarrhythmias.[40] The neurological changes with hypomagnesemia are nonspecific and include mental status changes and/or neuromuscular irritability. Tetany, one of the most striking and better known manifestations of Mg2+ deficiency, is only rarely seen; instead, less specific neurologic signs such as tremor, muscle twitching, bizarre movements, focal and/or generalized seizures, and delirium/coma are more common findings.[41]

While a low serum Mg2+ level is helpful and is typically indicative of low intracellular stores, normal serum Mg2+ values can still be observed in the face of a significant body deficiency of Mg2+ ; thus, serum Mg2+ determinations are an unreliable measure of total body Mg2+ balance.[42] Intracellular Mg2+ measurements, as well as other technologies, are available to assess Mg2+ balance, but are not readily available. A more practical measure of Mg2+ balance is the "magnesium loading test," which at the same time is both therapeutic and diagnostic. This test consists of the parenteral administration of magnesium sulfate and a time-wise assessment of urinary Mg2+ retention. This can be accomplished on an outpatient basis with the Mg2+ load being given in as short a time interval as 1 hour with subsequent urine collection over 24 hours. Individuals in a state of normal Mg2+ balance eliminate at least 75% of an administered load.[43]

Several issues arise concerning the treatment of diuretic-related hypomagnesemia beyond empirically normalizing a laboratory value. These include possible favorable effects on BP control, arrhythmia development, and/or coexisting electrolyte or neuromuscular symptoms. In the instance of BP control, there appears to be little additional reduction in BP when Mg2+ deficiency is corrected; this circumstance differs from the BP reduction occasionally seen when Mg2+ supplementation takes place in a nondeficient state. In the presence of refractory tachyarrhythmias or torsade de pointe, hypomagnesemia should be rapidly treated. Finally, when quantifiable measures, such as the electrolyte abnormalities of hypokalemia and/or hypocalcemia are present, the value of treating diuretic-related hypomagnesemia is readily apparent.

It is worthwhile for Mg2+ deficiency to be identified in all patients in whom a high index of suspicion for hypomagnesemia exists, but particularly in those with ischemic heart disease or known cardiac arrhythmias. In mild deficiency states, Mg2+ balance can often be reestablished by attention to the original causes (e.g., limiting diuretic and Na+ intake) and allowing dietary Mg2+ to correct the deficit. Parenteral Mg2+ administration, however, is the most effective way to correct a hypomagnesemic state, and should be the route used when replacement is of a more emergent nature. In the depleted patient, total body deficits of Mg2+ are typically in the order of 1-2 mEq/kg/BW. One commonly employed regimen, albeit empiric, gives 2 g of magnesium sulfate (16.3 mEq) IV over 30 minutes, followed by a constant infusion providing between 32-64 mEq/d until the deficit is presumed corrected.

A variety of oral Mg2+ salts are available for the treatment of hypomagnesemia. Mg2+ oxide is one commonly employed, but this salt is poorly soluble and acts as a cathartic, which can limit its effect. Mg2+ gluconate is the preferred salt for oral therapy, as this agent is very soluble and is minimally cathartic. Mg2+ carbonate is poorly soluble and does not appear to be as effective in reversing hypomagnesemia as is the gluconate salt. Oral Mg2+ is not recommended for therapy during acute situations, since the high doses needed almost always cause significant diarrhea. The IM route for Mg2+ administration is another route of delivery, albeit a potentially painful one, and should be avoided as long as IV access is readily available.[37]