Some patients are refractory to the usual dose of loop diuretics or become refractory after an initial response. Since these agents have a short half-life (2–6 hours), refractoriness may be due to an exces-sive interval between doses. Renal Na+ retention may be greatly increased during the time period when the drug is no longer active. After the dosing interval for loop agents is minimized or the dose is maximized, the use of two drugs acting at different nephron sites may exhibit dramatic synergy. Loop agents and thiazides in combination often produce diuresis when neither agent acting alone is even minimally effective. There are several reasons for this phenomenon.
First, salt reabsorption in either the TAL or the DCT can increase when the other is blocked. Inhibition of both can therefore produce more than an additive diuretic response. Second, thiazide diuretics often produce a mild natriuresis in the proximal tubule that is usually masked by increased reabsorption in the TAL. The combination of loop diuretics and thiazides can therefore block Na+ reabsorption, to some extent, from all three segments.
Metolazone is the thiazide-like drug usually used in patients refractory to loop agents alone, but it is likely that other thiazides would be as effective. Moreover, metolazone is available only in an oral preparation, whereas chlorothiazide can be given parenterally. The combination of loop diuretics and thiazides can mobilize large amounts of fluid, even in patients who have not responded to single agents. Therefore, close hemodynamic monitoring is essential. Routine outpatient use is not recommended. Furthermore, K+ wasting is extremely common and may require parenteral K+ administration with careful monitoring of fluid and electrolyte status.
Hypokalemia often develops in patients taking carbonic anhydrase inhibitors, loop diuretics, or thiazides. This can usually be man-aged by dietary NaCl restriction or by taking dietary KCl supple-ments. When hypokalemia cannot be managed in this way, the addition of a K+-sparing diuretic can significantly lower K+ excre-tion. Although this approach is generally safe, it should be avoided in patients with renal insufficiency and in those receiving angio-tensin antagonists such as ACE inhibitors, in whom life-threaten-ing hyperkalemia can develop in response to K+-sparing diuretics. It is not yet known whether adenosine receptor antagonists, which are K+-sparing diuretics (but which act primarily in the proximal tubule), will cause hyperkalemia.