Loop Diuretics in Cardiac Therapy
22:2

Loop Diuretics in Cardiac Therapy

Connie L. Barnes, Pharm.D.

Kellie L. Hager, Pharm.D. Candidate


Diuretics are a group of agents used to adjust the composition and volume of body fluids in numerous disease states. Loop diuretics are prescribed most commonly for the treatment of congestive heart and renal failure, cirrhosis, nephrotic syndrome and edema; newer agents have demonstrated benefit in the treatment of hypertension. Loop diuretics exert their effects in the thick ascending limb of the Loop of Henle (Figure 1).

Mechanism of Action

Loop diuretics primarily inhibit the sodium-potassium-chloride cotransport system located within the ascending limb of the Loop of Henle. Inhibition of this ion transport system prevents the reabsorption of these ions and a subsequent diuresis occurs.1 Although all loop diuretics have the same primary mechanism of action, various other actions of these agents differ. For example, furosemide and ethacrynic acid have demonstrated action in both the proximal and distal tubules, while bumetanide has exhibited indirect effects on the proximal tubule.2 Torsemide exerts no action at the proximal tubule, and this characteristic may account for the decreased kaliuresis observed with this agent.3

The mechanism of action of loop diuretics explains the common electrolyte abnormalities that often occur following administration; however, some of these agents predispose the patient to an increased amount of metabolic alterations. The elimination of potassium, hydrogen, calcium, magnesium, bicarbonate ammonium and possibly phosphate is enhanced following the administration of furosemide.1 Bumetanide also enhances the elimination of calcium, magnesium and phosphate in addition to its primary effects on the ioncotransport system.2

Torsemide is an anilinopyridine sulfonylurea derivative that has exhibited a pharmacologic property not demonstrated by other loop diuretics. Inhibition of chloride conductance from the peritubular surface of the nephron occurs with this particular agent. However, at the present time, the clinical relevance of this characteristic remains unproven.4

Indications

Due to their similar mechanism of action, all loop diuretics are indicated for several of the same disease states. Bumetanide, furosemide, torsemide and ethacrynic acid have all received FDA-approved indications for treatment of patients diagnosed with congestive heart failure. No single agent has proven clinically superior to furosemide, although bumetanide has proven efficacious in patients who develop an allergic reaction to or are unresponsive to furosemide.5 All four agents also have FDA-approved indications for use in renal failure; however, as in congestive heart failure, no significant benefits have been demonstrated when compared with furosemide.6

Other complications related to renal failure have been treated with loop diuretics; however, all agents have not received FDA approval for use in these complications. FDA has granted an indication to furosemide and bumetanide for treatment of massive edema experienced by patients living with nephrotic syndrome. Presently, furosemide is the only agent indicated for prevention of the progression of oliguria to anuria in children.1

Hypertension is an indication for which all four agents have been used, although only furosemide and torsemide have an FDA-labeled indication. Bumetanide, ethacrynic acid and torsemide provide an alternative drug regimen for patients intolerant to furosemide, while only torsemide has demonstrated potential clinical superiority over furosemide. Due to furosemide’s short duration of action and acute diuretic effects this agent is not often used for mild-to-moderate hypertension. Torsemide has exhibited a longer duration of action when compared to furosemide, which supports its beneficial use in the hypertensive population.7

Furosemide and bumetanide have FDA-approved indications for the treatment of edema; only furosemide has received an FDA indication for treatment of complications associated with acute pulmonary edema. Bumetanide has proven efficacious for the therapy of edema in patients intolerant to furosemide and subsequently has received an indication for use exclusively in this patient population. Pulmonary edema has been treated effectively with furosemide, ethacrynic acid and bumetanide, though the last agent has not been officially recognized by the FDA for this use.1

Although the primary actions of loop diuretics occur in the kidney, beneficial effects have been shown in patients diagnosed with hepatic complications. Bumetanide and torsemide have an FDA-approved indication for treatment of the edema and ascites associated with hepatic disease. Torsemide in combination with either an aldosterone antagonist or potassium-sparing diuretic, as well as ethacrynic acid alone, have received FDA approval for treatment of complications resulting from cirrhosis of the liver.1

Complete dosing information for specific disease states and product availability information is provided in TABLE 1.1

Table 1.
Dosing Information for Loop Diuretics
Drug Adult Oral Dosing Dosage Forms
Torsemide
Demadex (Boehringer Mannheim) 5 mg, 10 mg, 20 mg, 100 mg
Congestive Heart Failure/Chronic Renal Failure

Titrate dose by doubling dose until adequate diuresis is obtained. Single doses >200 mg have not been adequately studied.

Hepatic Cirrhosis
Initially 5 mg or 10 mg once daily in conjunction with an aldosterone antagonist or a potassium-sparing diuretic. Titrate to response by doubling the dose. Single doses >40 mg have not been adequately studied.

Hypertension Initially 5 mg once daily. May increase to 10 mg daily in 4–6 weeks if no response.

Tablets: Initially 10–20 mg daily.

Injection: 10 mg/ml
2 & 5 ml amps

Bumetanide
Bumex (Roche)
Hypertension
Initially 0.5–2 mg/day; if not adequate may repeat dose every 4–5 hours.
Tablets: .5 mg, 1 mg, 2 mg;

Injection: 0.25 mg/ml
2 mL amps & 2, 4,& 10 mL vials

Ethacrynic Acid
Edecrin (Merck)
Hypertension
Initially 50–200 mg daily in single or divided doses. Dosage adjustments in 25–50 mg increments. Doses of 200 mg twice daily have been administered in refractory edema.
Tablets: 25 mg, 50 mg

Powder for Injection:
50 ml vial for reconstitution

Furosemide (Various)
Lasix (Hoechst Marion Roussel)
Edema
20–80 mg initially; if no satisfactory response, readminister in 6–8 hours. Increase in increments of 20 mg or 40 mg until adequate diuresis. Maximum dose is 600 mg/d.

Hypertension
40 mg twice a day; adjust dose according to patient response.

CHF and Chronic Renal Failure 2–2.5 g/d

Tablets: 20 mg, 40 mg, 80 mg

Oral Solution: 10 mg/ml 60 ml, 120 ml

Oral Solution: 40 mg/5 ml 500 mL & UD 5 &10 ml

Injection: 10 mg/ml 2, 4, & 10 ml amps, single use vials & syringes

Adapted with permission from Facts and Comparisons

Loop diuretics have been effectively utilized for several years for their more common indications; however, numerous unapproved therapeutic uses also have been identified. One of the more interesting therapeutic uses is treatment of asthmatic patients. Inhaled furosemide has proven the most efficacious loop diuretic in the treatment of asthma; however, the exact mechanism by which it exerts its bronchial protective effects is unclear.

Bronchoconstriction in asthmatic patients results from alterations in bronchial osmolarity. Ion transport systems located in the patient’s airways regulate fluid and ion composition responsible for changes in osmolarity. Furosemide’s inhibition of the sodium-potassium-chloride cotransport system is currently theorized as the mechanism that allows this agent to exert its bronchial protective effects.8 Novembre et al.9 performed a randomized, placebo-controlled trial in 24 asthmatic children diagnosed with exercise-induced asthma. Nedocromil (4 mg) and inhaled furosemide (30 mg) were evaluated on both a combination and individual basis to determine the benefits in exercise-induced asthma. Data analysis determined that furosemide was equally effective as nedocromil while both agents demonstrated superiority to placebo. A later study published by the same team determined that furosemide’s protective effects against bronchoconstriction were demonstrated for two to four hours following administration.10

Although the benefits of furosemide have been demonstrated in a number of clinical trials thus far, further investigation is required to substantially determine its efficacy in the asthmatic population. All loop diuretics work by a similar mechanism of action; however, all other agents have demonstrated significantly less bronchoprotection in comparison with furosemide.11

A study conducted by Polosa et al. determined that furosemide (40 mg) has 2.5 times the bronchoprotective potency of bumetanide (2 mg) when evaluated in 12 asthmatic study participants.12 Characteristically, torsemide and bumetanide are more potent and lipophilic than furosemide. At present, it is not known if these properties account for the lesser efficacy of the newer agents in treating asthma.11

The reduction of nocturia in elderly patients has been identified as another therapeutic use for loop diuretics. Observations of elderly patients have found an increased excretion of urine during the night in comparison with daytime excretion. Pederson et al. evaluated the benefits of administering bumetanide four to six hours prior to bedtime in 28 patients aged 58–78 years. Bumetanide administered in 1 mg doses proved superior to a placebo regimen in reducing the number of nocturia events occurring weekly in these patients.13

Furosemide has shown beneficial effects as an adjunctive agent in the treatment of intracranial hypertension in patients undergoing surgery for intracranial hematomas or ruptured aneurysms. Samson et al. demonstrated a 56% reduction in intracranial pressure following intravenous administration of 80 mg of furosemide following induction of anesthesia in patients receiving aneurysm repair.14 Furosemide’s ability to control intracranial pressure has been related to the carbonic anhydrous benefit of reducing cerebral spinal fluid production, its effects on central venous pressure and its ability to induce diuresis.15

More recently, the use of continuous infusion loop diuretics has attracted tremendous attention. This method has proven beneficial in patients with a diuretic resistance or tolerance to conventional intermittent therapy.16 Several potential advantages of continuous infusion loop diuretics have been identified, including decreased electrolyte loss secondary to a lower dosage of diuretic, production of a more reliable urine flow and decreased alterations in fluid balance.17 Patients with congestive heart failure, chronic renal insufficiency, postcardiac surgery and cyclophosphamide-induced antidiuresis participated in clinical trials to evaluate the benefits of this treatment method.18

As a result of these studies, several potential adverse reactions have been identified. The effects of loop diuretics on both water and electrolytes predispose the patient to the majority of the unwanted adverse effects. Hypokalemia was found to be the most common adverse reaction in patients treated with high-dose furosemide.19 Supraventricular tachycardia,20 myalgia21 and elevated uric acid concentrations22 have also occurred in patients treated with continuous infusion loop diuretics. Although further studies are needed to firmly establish the benefits of continuous infusion loop diuretics, health professionals should be educated on their potential benefit as a therapeutic alternative.

Pharmacokinetics

Kinetic profiles for loop diuretics share many similarities, although differences exist that warrant consideration. All loop diuretics undergo metabolism to varying degrees and are excreted primarily through the urine. Protein binding exceeds 90% for all available loop diuretics. The different kinetic characteristics of loop diuretics are presented in TABLE 2.1

Table 2.
Different Kinetic Characteristics of Loop Diuretics
Diuretic
(Oral)
Bioavailability
(%)
Half-Life
(min)
Onset of Action
(min)
Duration
(hr)
Relative Potency
Furosemide 60–64 ~120 within 60 6–8 1
Ethacrynic acid ~100 60 within 30 6–8 0.6–0.8
Bumetanide 72–96 60–90 30–60 4–6 ~40
Torsemide ~80 210 within 60 6–8 2–4
Adapted with permission from Facts and Comparisons

Warnings/Precautions

Loop diuretics offer numerous beneficial effects in the management of commonly encountered disease states. Unfortunately, several warnings and precautions need to be considered when evaluating these agents as a therapeutic option.

Excessive diuresis has resulted from the use of loop diuretics, predisposing the patient to a number of complications. Rapid diuresis has resulted in dehydration, hypotensive episodes and hemoconcentration, which often produces thromboembolic episodes. Although thromboembolic events occur primarily in elderly patients, all patients should be closely monitored. Diarrhea also has been reported; however, it has occurred primarily with ethacrynic acid and in children consuming furosemide at higher doses. Periodic examinations also should be performed to evaluate potential electrolyte imbalances, including hypokalemia, hypomagnesemia, hypocalcemia, hyponatremia and hypochloremia. Patients with hepatic cirrhosis and ascites are at an increased risk for electrolyte disturbances and should be monitored closely during therapy for any clinical indications of this abnormality.1

Several hearing complications including tinnitus, irreversible and reversible hearing impairment, deafness and a sense of ear fullness have been observed with loop diuretic therapy. Often these complications occur as a result of rapid injection, severe renal impairment, increased dosage and combination therapy with other ototoxic agents.1

Discontinuation of therapy is recommended when elevations in blood urea nitrogen or creatinine, oliguria or azotemia occur due to therapy.1

Drug Interactions

Loop diuretics have exhibited their ability to potentiate both therapeutic and detrimental effects on a number of medications. Increased plasma levels and toxicity often result from the concomitant use of loop diuretics and other medications. These agents have the potential to increase plasma levels and toxicity of lithium. Furosemide exclusively has shown to increase plasma levels of propranolol. Enhanced anticoagulation effects also have resulted from concomitant administration of loop diuretics and anticoagulants. Another interaction of concern is encountered with aminoglycosides. Ototoxicity has been demonstrated with both loop diuretics and aminoglycosides; therefore, concomitant use of these agents has been shown to increase auditory toxicity.1

Transient diaphoresis, hot flashes, hypertension, tachycardia and nausea may occur as a result of concurrent use of chloral hydrate and loop diuretics, although the incidence of these effects is rare. Patients on concurrent digitalis–loop diuretic therapy should receive extensive monitoring for electrolyte imbalances that could potentiate a digitalis-induced arrhythmia.1

In contrast to loop diuretics potentiating the effects of other medications, documentation exists that shows enhanced diuretic actions by other agents. Unwanted additive ototoxic effects have occurred when cisplatin and loop diuretics are used within the same regimen. Furosemide’s diuretic response is exaggerated by the concomitant use of clofibrate. A profound diuresis often resulting in electrolyte disturbances has occurred with thiazide–loop diuretic combinations.1

Loop diuretics possess the ability to decrease glucose tolerance in certain patient populations. Therefore, hyperglycemia has occurred in patients treated with sulfonylureas following the addition of a loop diuretic to their medication regimen.1

Several agents when used in combination with loop diuretics result in a decreased diuretic effect. Nonsteroidal anti-inflammatory agents, probenecid and salicylates have all resulted in an impaired diuretic response. Charcoal and phenytoin also have demonstrated the potential to decrease the diuretic effects of furosemide.1

Most drug interactions with loop diuretics are predictable; however, concurrent administration of certain agents with loop diuretics may produce unpredictable effects. Antagonism or potentiation of the effects of nondepolarizing muscle relaxants and theophylline may result following the use of these agents in combination with loop diuretics. Effects demonstrated with nondepolarizing muscle relaxants may be determined by the dose of loop diuretic administered; however, this theory remains to be demonstrated by clinical trials.1

Adverse Effects

Numerous adverse effects have resulted following administration of the loop diuretics. Although all loop diuretics work in a similar manner, their side effects profiles differ significantly and should be considered before selecting a particular agent.

Metabolic abnormalities are a common occurrence in patients receiving treatment with loop diuretics. Hypokalemia, hypocalcemia, hypovolemia and hyponatremia have been associated with the use of all these agents. However, one of the newer agents, torsemide, has shown minimal effects on sodium and potassium and may actually have a calcium-sparing effect.23 Reports of hyperuricemia followed clinical trials with bumetanide (18.4%), ethacrynic acid and furosemide, although exact percentage values are unknown for ethacrynic acid and furosemide. Torsemide again proved superior to these agents with no or slight increases in uric acid levels following administration during clinical trials.24

Cardiovascular events have been documented in patients using loop diuretics with the most common adverse event presenting as orthostatic hypotension. In addition, electrocardiographic changes and chest pain also have been reported following the use of loop diuretics.1

Dermatologic events comprise another adverse effect incurred with loop diuretics. All agents, excluding torsemide, have shown the potential to produce hives, rashes and itching in patients.1 More serious adverse events including interstitial nephritis, systemic vasculitis and exfoliative dermatitis have been reported following high-dose furosemide use in renal failure patients.25

Central nervous system reactions, including headache, dizziness and blurred vision, have developed in some patients utilizing these agents. Alterations in hearing function, including tinnitus and hearing loss, have occurred with all agents except torsemide. To date, no cases of ototoxicity have been documented with torsemide.1

Also, hematologic conditions, including anemia, thrombocytopenia and agranulocytosis, have been documented with furosemide use, while severe neutropenia has occurred in patients prescribed ethacrynic acid.1 Torsemide has demonstrated significant alterations in red blood cell count, hemoglobin concentration and packed cell volume.26

Several miscellaneous adverse effects have resulted from the use of these particular agents. Jaundice has been reported with both furosemide and ethacrynic acid. Severe cases of watery diarrhea, often warranting treatment discontinuation, have occurred with the use of ethacrynic acid. The incidence of excessive urination (6.7%) in clinical trials conducted on patients treated with torsemide is also of interest.1

Adverse effect profiles for loop diuretics vary depending on the dosing regimen utilized and specific disease state being treated.1 Prevention of these side effects is extremely important. Adequate monitoring of a patient’s medication regimen and laboratory data is essential to avoid the development of adverse reactions.

Place in Therapy

Varying properties and characteristics among the loop diuretics account for potential advantages of one particular agent over another. Furosemide and ethacrynic acid have demonstrated numerous potential therapeutic uses throughout their extensive existence. However, use of the latter agent has virtually ceased because of lack of benefit and increased side effects when compared to its counterparts.25 Furosemide is currently effective in the treatment of several disease states, including renal failure, hepatic disease and edema associated with congestive heart failure. Some benefit in the treatment of hypertension has been demonstrated, although it is recommended that furosemide be reserved for patients with thiaziderefractory fluid retention or patients experiencing impaired renal function.27

Bumetanide has shown potential benefit in furosemideresistant patients and in those individuals who have developed an allergic response to furosemide and thus has primarily been utilized in this patient population.

In comparison with furosemide, torsemide has demonstrated several potential clinical advantages, including a greater potency, longer duration of action, greater bioavailability and decreased effects on certain electrolytes and uric acid levels. As mentioned earlier in relation to furosemide, loop diuretics are often reserved for a hypertensive crisis or for patients refractory to other antihypertensive agents. Due to its increased half-life and minute effects on potassium and metabolic parameters, low-dose torsemide has been suggested as a potential first-line agent in the treatment of hypertension.7 Torsemide also has shown possible benefit as an alternative agent in patients refractory or hypersensitive to furosemide. Although bumetanide is approved for treating this patient population, further clinical trials are necessary to prove torsemide’s usefulness in this arena.

An injectable form of the loop diuretic piretanide is currently under investigation by Hoechst Marion Roussel. Clinical trials completed to date have demonstrated no potential benefits of this agent when compared with either furosemide or bumetanide. Continued clinical research is necessary to evaluate the potential advantages of this particular loop diuretic.28

Conclusion

Loop diuretics have existed as a beneficial treatment modality for decades. Experience with older agents and recognition of their disadvantages prompted the development of bumetanide and torsemide. Although the newer loop diuretics have demonstrated potential in a number of disease states, adequate clinical evaluation is imperative to determine clinical and economic superiority to the prototype agent.


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