Why is it important to check potassium level before furosemide administration

Introduction

Furosemide, an anthranilic acid derivative, is a rapid acting, highly efficacious diuretic Rankin (2002). Its mechanism of action is inhibition of the sodium-potassium-2 chloride (Na+-K+-2 Cl−) co-transporter (symporter) located in the thick ascending limb of the loop of Henle in the renal tubule Jackson (1996). Furosemide is classified as a loop diuretic and, because of is marked efficacy, a as a high ceiling diuretic.

Furosemide is administered either p.o. or i.v. Its onset of action is rapid (< 1 hour), and its effects persist for up to eight hours. Up to 80% of an administered dose of furosemide is excreted unchanged in urine. It is used for the treatment of edematous states, such as those associated with congestive heart failure or cirrhosis of the liver, and for the treatment of hypertension, as a monotherapy or in combination with other antihypertensive drugs. Adverse effects of furosemide are often related to the increased excretion of electrolytes. The development of hypokalemia is a serious toxicity that can, for example, potentiate the cardiac effects of digitalis. Prolonged administration of furosemide can lead to ototoxicity, hyperglycemia, and elevated blood LDL cholesterol and triglyceride levels.

Pharmacology and mechanism of action

Furosemide is a loop diuretic that inhibits the Na+/K+/2Cl- cotransporter in the ascending thick loop of Henle. It is often called a high-ceiling diuretic because it is more effective than other diuretics. Furosemide decreases the sodium, chloride, and potassium reabsorption from the tubule. Subsequently, these ions are retained in the renal tubule and presented to the distal nephron. Dilute urine is produced because water is retained in the tubule when it reaches the distal tubule. In addition, there is an associated urine loss of Mg++ and Ca++. An additional mechanism of action is via prostaglandin synthesis. Furosemide increases intrarenal prostaglandin production (e.g., PGI2), which increases renal blood flow. Synthesis of prostaglandins also may cause vasodilation in other tissues. The plasma half-life in animals is short (1.5-3 hours); therefore this is a short-acting drug, with a maximum onset of effect of 1-2 hours, and duration of 2-4 hours. Oral absorption can be highly variable, but in dogs is as high as 77%. Subcutaneous absorption is as high as other injectable routes. In horses, oral absorption is so low that this is not a viable method of administration.

Increased Oxidative Stress in Acute Kidney Injury

Furosemide is sometimes used in patients with acute kidney injury (AKI) to increase urine output. However, it remains uncertain whether risks of therapy outweigh benefits in this patient population. Silbert and colleagues conducted a study in 30 critically ill patients with AKI treated with furosemide to assess the effect of furosemide on oxidative stress. Urine and plasma levels of F2-isoprostanes, markers of oxidative stress, were measured before and after furosemide use. Urine F2-isoprostane levels were found to be positively correlated with urine furosemide levels (P = 0.001). Furosemide-induced increase in urine F2-isoprostanes varied by severity of AKI (P < 0.001) and was greatest in those patients with the most severe AKI. However, no effects on plasma F2-isoprostane levels were observed with furosemide use. According to Silbert et al. this was the first study demonstrating increased renal oxidative stress with furosemide use in AKI. Follow-up randomized controlled trials are needed to further elucidate the significance of this adverse drug reaction with furosemide therapy and to determine whether benefits of furosemide use outweigh the risks in patients with AKI [9c].

Fractures in children with congenital heart disease

Furosemide has been shown to be associated with increased risk for fractures in adult patients. A meta-analysis of fracture risk in adult loop diuretic users in comparison to non-loop diuretic users showed a 15% increased risk for total fractures among furosemide users. Furosemide and other loop diuretics cause increased urinary excretion of calcium resulting in decreased bone mineral density and risk for osteoporosis. While more commonly used in adults, furosemide has a role in the treatment of children with congenital heart disease (CHD) and cardiomyopathies when symptoms of heart failure develop. Heo and colleagues conducted a retrospective cohort study to evaluate the association between furosemide use and fracture development in children with CHD. 3912 patients under age 12 with CHD, cardiomyopathy, or heart failure were included in the study, with 254 in the furosemide-adherent group, 724 in the furosemide-nonadherent group, and 2934 in the furosemide nonusers group. Both the furosemide-adherent and nonadherent groups had prescriptions for furosemide, but the nonadherent group had a medication possession ratio of < 70%. The incidence of fractures was highest among furosemide-adherent patients (9.1%; 23 of 254), followed by the furosemide-nonadherent patients (7.2%; 52 of 724), and furosemide nonusers (5%; 148 of 2934) (P < 0.001). Using logistic regression, both furosemide groups were more likely to experience fractures when compared to nonusers of furosemide with an OR of 1.9 (95% CI 1.17–2.98; P = 0.009) for the furosemide-adherent group and an OR of 1.5 (95% CI 1.10–2.14; P = 0.01) in the furosemide-nonadherent group. Additionally, in the Cox proportional hazard model, there was a significantly higher risk of fractures among furosemide-adherent patients compared to nonfurosemide users (HR 1.6; 95% CI, 1.00–2.42; P = 0.04). This study showed that pediatric patients with CHD on chronic furosemide therapy were nearly twice as likely to experience a fracture as pediatric patients with CHD not using furosemide therapy. This should be taken into consideration when making decisions regarding long-term diuretic use in pediatric patients. When loop diuretic therapy is needed, efforts should be made to use them at the lowest dose and shortest duration necessary [15MC].

Special considerations

Furosemide injection contains the sodium salt of furosemide that is formed by the addition of sodium hydroxide during manufacturing. It should be stored at a temperature of 15–30°C and protected from light. Injections having a yellow color have degraded and should not be used. Exposure of furosemide tablets to light may cause discoloration. Discolored tablets should not be used. Furosemide injection can be mixed with weakly alkaline and neutral solutions having a pH of 7–10, such as 0.9% saline or Ringer's solution. A precipitate may form if the injection is mixed with strongly acidic solutions such as those containing ascorbic acid, tetracycline, adrenaline (epinephrine) or noradrenaline (norepinephrine). Furosemide injection should also not be mixed with most salts of organic bases, including lidocaine, alkaloids, antihistamines and morphine.

Diuretics

Furosemide is a loop diuretic; it blocks the Na+/K+/2Cl− cotransporter in the ascending limb of the loop of Henle, which promotes natriuresis and diuresis. The aim of furosemide administration is to turn oliguric renal failure into non-oliguric renal failure, which facilitates the management of fluid and electrolyte status. The efficacy of furosemide in treating horses with acute renal failure is not documented. In human patients with ARF, administration of furosemide does not affect the long-term outcome. The use of furosemide is contraindicated in horses with suspected urinary tract obstruction or rupture.

Mannitol is an osmotic diuretic that increases intravascular osmolality, causing an increase in intravascular volume and, as a consequence, it increases renal blood flow and glomerular filtration rate. These osmotic effects cause an increase in urinary output and may be effective in the treatment of ARF characterized by tubular obstruction and swelling of the tubular cells.88