Pharmacokinetics of metolazone in normal subjects and in patients with cardiac or renal failure

Tilstone, W. J.; Dargie, H. J.; Dargie, Elizabeth N.; Morgan, Hugh; Kennedy, A. C.

doi:10.1002/cpt1974162322

Cited by 55 publications

(22 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This has been shown for digoxin (Oliver, Tazman & Frederickson, 1973), hydrochlorothiazide (Anderson, Brettell & Aikawa, 1961;Beermann & Groschinsky-Grind, 1979) and metolazone (Tilstone, Dargie, Dargie, Morgan & Kennedy, 1974) in which the rate and/or extent of gastrointestinal absorption of these drugs were diminished in the heart failure patient. Crouthamel (1974Crouthamel ( , 1975, analyzing the date of Bellet, Roman & Boza (1971), has suggested that the rate and extent of oral quinidine absorption is also decreased in patients with congestive heart failure.…”

Section: Introductionmentioning

confidence: 78%

Bioavailability of quinidine in congestive heart failure.

Ueda¹,

Dzindzio²

1981

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 The oral bioavailability of quinidine was evaluated in eight patients with moderate to severe congestive heart failure. Each patient was given a 400 mg dose of quinidine gluconate by intravenous infusion and orally in solution. Serial plasma samples and total urine for drug analysis were collected for 24 and 48 h after drug administration, respectively. 2 When compared to control cardiac patients, the rate of quinidine absorption was slower in the heart failure patients. The mean value for the apparent absorption half-life and time to achieve peak plasma quinidine concentration was 38 + 18 min and 2.4 + 1.5 h, respectively. The corresponding values observed in the control subjects were 18 + 6 min and 1.0 + 0.6 h. 3 The extent of quinidine absorption when evaluated by the AUC and urinary excretion methods was about 72% of the administered dose in the congestive heart failure patients. This value was similar to the extent of quinidine absorption (approximately 73%) observed in the control subjects. 4 A reduction in the plasma clearance rate and apparent volume of distribution for quinidine was observed in the congestive heart failure patients. 5 When compared with non-heart failure cardiac patients, the results of this study suggest that patients with congestive heart failure may require smaller oral quinidine dosages to achieve therapeutic drug concentrations in the plasma or serum.

show abstract

Section: Introductionmentioning

confidence: 78%

Bioavailability of quinidine in congestive heart failure.

Ueda¹,

Dzindzio²

1981

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Physiologically this seems like an attractive approach to decongestion, one that is supported in the current heart failure practice guidelines, despite no randomized trials comparing combination diuretic therapy with a thiazide to loop diuretics alone 4. In fact, most studies examining metolazone use in HF are small, single‐center retrospective analyses without a control arm, published over 25 years ago, that focused on end points like urinary volume and sodium concentration as opposed to clinical outcomes 8, 10, 28, 29. Nevertheless, the cumulative existing evidence in only 350 patients does illustrate that metolazone produces a 3‐fold increase in natriuresis, increases weight loss and improves diuresis in patients who were previously not suitable for hospital discharge 7, 8, 9, 10, 28, 29, 30…”

Section: Discussionmentioning

confidence: 99%

Outcomes Associated With a Strategy of Adjuvant Metolazone or High‐Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis

Brisco‐Bacik

Maaten

Houser

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundIn acute decompensated heart failure, guidelines recommend increasing loop diuretic dose or adding a thiazide diuretic when diuresis is inadequate. We set out to determine the adverse events associated with a diuretic strategy relying on metolazone or high‐dose loop diuretics.Methods and ResultsPatients admitted to 3 hospitals using a common electronic medical record with a heart failure discharge diagnosis who received intravenous loop diuretics were studied in a propensity‐adjusted analysis of all‐cause mortality. Secondary outcomes included hyponatremia (sodium <135 mEq/L), hypokalemia (potassium <3.5 mEq/L) and worsening renal function (a ≥20% decrease in estimated glomerular filtration rate). Of 13 898 admissions, 1048 (7.5%) used adjuvant metolazone. Metolazone was strongly associated with hyponatremia, hypokalemia, and worsening renal function (P<0.0001 for all) with minimal effect attenuation following covariate and propensity adjustment. Metolazone remained associated with increased mortality after multivariate and propensity adjustment (hazard ratio=1.20, 95% confidence interval 1.04–1.39, P=0.01). High‐dose loop diuretics were associated with hypokalemia and hyponatremia (P<0.002) but only worsening renal function retained significance (P<0.001) after propensity adjustment. High‐dose loop diuretics were not associated with reduced survival after multivariate and propensity adjustment (hazard ratio=0.97 per 100 mg of IV furosemide, 95% confidence interval 0.90–1.06, P=0.52).ConclusionsDuring acute decompensated heart failure, metolazone was independently associated with hypokalemia, hyponatremia, worsening renal function and increased mortality after controlling for the propensity to receive metolazone and baseline characteristics. However, under the same experimental conditions, high‐dose loop diuretics were not associated with hypokalemia, hyponatremia, or reduced survival. The current findings suggest that until randomized control trial data prove otherwise, uptitration of loop diuretics may be a preferred strategy over routine early addition of thiazide type diuretics when diuresis is inadequate.

show abstract

“…Additionally, a decrease in sodium-and chloride reabsorption is seen in the proximal convoluted tubules without carbonic anhydrase inhibition [13][14][15]. Presumably as a consequence of the drug action in the proximal tubule, metolazone, in contrast to other thiazides, is able to produce a diuresis despite of a low glomerular filtration rate [9,16]. Severe congestive HF is often accompanied by a degree of renal failure due to low cardiac output making the use of metolazone attractive in fluid overload management in HF.…”

Section: Site Of Actionmentioning

confidence: 99%

“…The study included only three HF patients and apparently, no other studies have evaluated the fractional absorption of metolazone in HF patients. The rate of absorption of metolazone is lower in patients with cardiac or renal failure when compared to normal subjects [9]. Metolazone is excreted mainly in the urine, approximately 70-95% being unchanged [10,11].…”

Section: Absorption and Metabolismmentioning

confidence: 99%