Why should a diuretic that decreases plasma K+ levels not be used with digoxin?

Human Pharmacokinetics

Loop diuretics are most commonly given by mouth. They are also given intravenously for rapid effects such in such disorders as acute pulmonary edema. Bumetanide, ethacrynic acid, and torsemide are well absorbed from the gastrointestinal tract, with absorption at a predictable percent: bumetanide ∼80%, ethacrynic acid ∼100%, and torsemide ∼80%. The absorption of furosemide is ∼60% but the absorption percent is much more variable from patient to patient Jackson (2006). About 65% of the administered dose of each loop diuretic is excreted unchanged in the kidney, with the exception of torsemide which is highly metabolized (∼80%) in the liver. The elimination t1/2 of torsemide (∼3.5 hrs) is the longest of the four loop diuretics. The half-lives of the other three range from about 1–1.5 hr. The reality of short half-lives of the four loop diuretics compared to other diuretics, for instance many of the thiazide type, has important clinical implications. Optimal diuretic effects often require frequent dosing because the effects of the drugs can wear off between doses during chronic therapy such as in treating hypertension.

Loop diuretics are highly bound to plasma protein, mainly albumin. Only a small percentage of the loop diuretic in the plasma enters the luminal fluid of the kidney through glomerular filtration. Rather most of each drug is actively secreted by organic acid transport system in the proximal tubule. Further down the nephron, the loop diuretic has its effect on the luminal border of the thick ascending limb of the loop of Henle.

Loop Diuretics

Loop diuretics are the most potent diuretics that reduce ECF, cardiac output, and blood pressure. The mechanism of action for loop diuretics like furosemide is by inhibiting the apical sodium/potassium/chloride transporter in the thick ascending limb of the loop of Henle. Unlike thiazide diuretics, loop diuretics cannot be used as first-line antihypertensive therapy and use is limited in patients with kidney disease. Loop diuretics are very effective for edema in hypertensive patients due to their ability to act quickly and cause large reductions in ECF. Adverse effects for loop diuretics are like thiazide diuretics and include hyponatremia, hypokalemia, and alkalosis. One notable adverse loop diuretic effect is increased calcium excretion; hence, loop diuretics are not suitable for hypertensive patients with osteoporosis.

Sarcopenia

Loop diuretics have been shown to increase the risk of bone loss and fractures. Ishikawa et al. set out to determine the prevalence and risk factors for sarcopenia in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) with a focus on drugs. They conducted a cross-sectional analysis of 260 patients with NDD-CKD between June 2016 and March 2017 and analyzed the association of sarcopenia and various patient factors, such as, drug use, age, and gender. In total, 25% (65) of study participants had sarcopenia. Patient factors found to have a significant association with sarcopenia diagnosis included age, male gender, body mass index, diabetes mellitus, and loop diuretic therapy (OR 4.59, 95% CI 1.81–11.61; P-value = 0.001). Given the increased risk of sarcopenia in patients receiving loop diuretics, benefits and risks of prolonged loop diuretic therapy should be considered. Additionally, when loops diuretics are needed, they should be used for the shortest duration of time necessary [8C].

Loop Diuretics

Loop diuretics (e.g., furosemide, bumetanide, torsemide, and ethacrynic acid) are organic anions that enter the tubular lumen primarily through secretion by the organic anion secretory system of the proximal tubule (see Chapter 4). They directly inhibit Na+ reabsorption by the thick ascending limb of Henle’s loop by blocking the Na+-K+-2Cl− symporter located in the apical membrane of these cells (see Chapter 4). By this action, they not only inhibit Na+ reabsorption but also disrupt the ability of the kidneys to dilute and concentrate the urine. Dilution is impaired because solute (NaCl) reabsorption by the water-impermeable thick ascending limb of Henle’s loop is inhibited. NaCl reabsorption by the medullary portion of the thick ascending limb also is critical for the generation and maintenance of an elevated medullary interstitial fluid osmolality. Therefore inhibition of NaCl transport by loop diuretics results in a decrease in the osmolality of the medullary interstitial fluid. With a decrease in medullary interstitial fluid osmolality, water reabsorption from the collecting duct is impaired, and the concentrating ability of the kidneys is reduced. Water reabsorption from some portions of the thin descending limb of Henle’s loop also is impaired by loop diuretics, again because of the decrease in medullary interstitial fluid osmolality. This decrease in thin descending limb water reabsorption accounts in part for the increase in water excretion seen with loop diuretics.

Loop diuretics are the most potent diuretics available, increasing the excretion of Na+ to as much as 25% of the amount filtered. This large natriuresis reflects the fact that the thick ascending limb normally reabsorbs approximately 20% to 25% of the filtered Na+ and that downstream segments of the nephron have a limited ability to reabsorb the excess Na+ delivered as a consequence of loop diuretic action.

Loop Diuretics

Loop diuretics such as furosemide, ethacrynic acid, and bumetadine (i.e., those with primary action on the loop of Henle in the kidney) produce rapid, acute, but reversible auditory changes. A common clinical complaint is tinnitus, but there are also notable threshold shifts for sound sensation across all frequencies. The stria vascularis is notably edematous; characteristic features include swelling of marginal cells, shrinkage of intermediate cells, and dilation of the intercellular spaces rapidly following intravenous dosing. The loop diuretics directly affect the stria vascularis from the vasculature, resulting in rapid onset. The edema is due to inhibition of ion transport by Na+/K+-ATPases at the basolateral membranes of marginal cells, resulting in osmotic expansion of those cells and the intercellular spaces. The toxicologic mechanism of hearing loss related to loop diuretics is due to attenuation of the endocochlear potential and not from injury of the hair cells. Macrolide antibiotics, such as erythromycin, produce similar but less severe changes. The mechanism for erythromycin’s effects has not been elucidated.

Musculoskeletal

Although loop diuretics increase renal calcium excretion, there have been variable results in studies of their effects on the risk of fractures. In a case–control study of the risk of fracture in 44 001 patients who had taken a loop diuretic in the preceding 5 years and 194 111 age- and sex-matched controls, “ever” use of a loop diuretic was associated with a crude 51% increased risk of any fracture (OR = 1.51; 95% CI = 1.48, 155) and a 72% increased risk of hip fracture (OR = 1.72; 95% CI = 1.64, 181) [40]. After adjustment for potential confounders, the risk reduction was only slightly increased for any fracture (OR = 1.04) and for hip fracture (OR = 1.16). With an increased average daily dose the estimates increased in former users but fell in current users. Furosemide was associated with higher risk estimates than bumetanide. This study does not provide a definitive answer to the risk of fractures with loop diuretics but suggests that particular caution should be taken.

Increased mortality with continuous infusion vs bolus injection

Loop diuretics remain a mainstay in both the chronic and acute heart failure to improve symptoms of fluid overload, however, there has been no consensus on whether loop diuretics administered via continuous intravenous infusion conferred greater benefit over intermittent bolus injection. To answer this question, Sager et al. performed a small single-center study at a university hospital where 40 elderly patients (mean age > 80 years old) with advanced heart failure (NYHA class III and IV) were randomly divided into two groups to receive furosemide, either an intravenous bolus group or an intravenous continuous infusion. Furosemide bolus injections were given one or several times daily (total daily doses 20–100 mg), whereas continuous infusions were typically between 4 and 10 hours a day at doses ranging from 100 to 500 mg. High levels of NT-proBNP have been associated with increased mortality in HF patients. While in this study, naturetic peptide, NT-proBNP in both severe heart failure groups were reduced by a similar extent by the two interventions, the study found a significantly higher mortality at 3 months after discharge in the group of patients receiving furosemide continuous infusion compared with the bolus injections (40% dead vs 10% dead, P = 0.03, respectively) (Sager et al., 2020) [c].

Drug Interactions

Loop diuretics may decrease lithium clearance, resulting in lithium toxicity. Use with angiotensin-converting enzyme inhibitors may result in a precipitous fall in blood pressure, especially in the presence of Na+ depletion. Diuretic-induced hypokalemia may increase the risk of digoxin toxicity; this occurs because digoxin binds to the K+-site of the Na+/K+-adenosine triphosphatase (ATPase) pump. Under conditions of hypokalemia, there is less K+ competing with digoxin and digoxin toxicity may occur. Concomitant use with nonsteroidal antiinflammatory drugs reduces the blood pressuring–lowering effects of diuretics owing to the Na+ reabsorption associated with nonsteroidal antiinflammatory drugs.

Acute and Short-Term Toxicity

Loop diuretics and increasing salt intake

Loop diuretics (e.g., furosemide) decrease the reabsorption of Na+ and Cl− ions in the thick ascending limb of the loop of Henle and hence decrease the effective medullary interstitial osmolality. A small dose of furosemide is needed to achieve this purpose, but because of its short duration of action, furosemide may need to be given twice daily. If as a result of this intervention the urine effective osmolality were to decrease to 300 mosmol/kg H2O, and if the intake of NaCl were to be increased to 200 mmol/day, the number of effective osmoles to excrete would be 500 mosmol/day (400 mosmol of NaCl and 100 mosmol of K+ ions with an anion); therefore, the urine volume will increase to 500 mosmol/300 mosmol/L = 1.7 L/day.