Q:  I am a nurse in a CKD clinic and I have noticed the practice of instructing patients to take metolazone 30 to 60 minutes prior to taking a loop diuretic such as furosemide for resistant edema. What is the evidence to support this pre-dosing practice?

A: Loop diuretics work by inhibiting sodium reabsorption in the nephron at the loop of Henle. Despite the usual efficacy of loop diuretics, diuretic resistance can be observed in clinical scenarios such as congestive heart failure (CHF), chronic kidney disease (CKD) and cirrhosis of the liver. In addition to disease-related resistance, a potential mechanism for diminished response to loop diuretics is diuretic tolerance. With chronic loop diuretic therapy, an increased amount of sodium continuously escapes the loop of Henle and is presented to the distal nephron. Over time this can lead to hypertrophy of distal convoluted tubule (DCT) cells and increased distal sodium reabsorption, thus negating the proximal effects of the loop diuretic. Since metolazone and thiazides block sodium reabsorption at the DCT, these drugs can restore efficacy in the diuretic-resistant patient (Brater, 1998). Metolazone is often used as the preferred agent because of its potency and extended half-life (t 1/2 = 20 hrs; dependent on renal function), which provides prolonged efficacy with once a day dosing. However, there is no evidence that metolazone is superior to thiazide diuretics (Ellison, 1991).

Compensation of the DCT is the main reason for prescribing loop diuretic and thiazide combinations for patients that fail to achieve resolution of edema with one diuretic alone. Commonly, furosemide and metolazone are used in combination, and much evidence supports the efficacy and safety of this combination (Ghose & Gupta, 1981; Gunstone, Wing, Shani, Njemo & Sabuka, 1971; Arnold, 1984; Grosskopf, Rabinovitz & Rosenfeld, 1986; Segar, Robillard, Johnson, Bell & Chemtob, 1992; Cachero, Lofland, Springate & Feld, 1990; Brown, & MacGregor, 1981; Bamford, 1981; Allen, Hind & McMichael, 1981; Marone, Muggli, Lahn & Frey, 1985; Garin, 1987). Interestingly, pre-dosing of oral metolazone 30-60 minutes prior to furosemide is common practice and has been recommended to maximize the efficacy of this approach (Ellison, 1991).

A Medline literature search was conducted to identify reports of combined loop diuretic and metolazone therapy to determine if there is evidence to support the recommendation to pre-dose metolazone. Ten literature reports (see Table 1) describing combined loop diuretic and metolazone therapy were identified. Interestingly, in none of these reports is the timing of metolazone administration relative to the loop diuretic indicated.

A study by Steinmuller and Puschett (1972) found that peak diuretic effect occurs approximately 80 minutes after an oral metolazone dose, which does provide a rationale for the recommendation to pre-dose oral metolazone (1972). However, this study included only two healthy volunteers who received a single 2.5 mg dose and did not receive a loop diuretic. Of note, the only published recommendation for pre-dosing occurred in a review article that stated, “When a second diuretic is combined with a loop diuretic, the second drug is best given before the loop diuretic (1 hour is reasonable for metolazone)” (Ellison, 1991). This recommendation was referenced with the study by Steinmuller and Puschett (1972) as the citation.

Published studies evaluating the efficacy of loop diuretic and metolazone combinations have shown the combination to be safe and effective. Hypokalemia is the most commonly reported side effect and patients receiving this regimen should be carefully monitored to avoid excessive diuresis and hypokalemia. The timing of metolazone, in relation to loop diuretic administration, was not shown to be a clinically important factor in these studies. Although the study by Steinmuller and Puschett (1972) provides a pharmacodynamic rational for pre-dosing metolazone, no published clinical studies have compared pre-dosing to simultaneous dosing. Based on the review of the literature, the recommendation for pre-dosing metolazone appears to be based solely on the delayed onset of action observed following a single orally administered metolazone dose. Given the lengthy half-life of metolazone, this delayed onset is unlikely to be a concern during ongoing chronic treatment, particularly once steady-state is achieved. There does not appear to be any reason to discourage pre-dosing metolazone during chronic therapy, except for the increased complexity and inconvenience of the regimen. The conclusion is that the practice of pre-dosing metolazone prior to a loop diuretic is not supported by the literature.