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      Clinical Pharmacology of Furosemide in Neonates: A Review

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          Abstract

          Furosemide is the diuretic most used in newborn infants. It blocks the Na +-K +-2Cl symporter in the thick ascending limb of the loop of Henle increasing urinary excretion of Na + and Cl . This article aimed to review the published data on the clinical pharmacology of furosemide in neonates to provide a critical, comprehensive, authoritative and, updated survey on the metabolism, pharmacokinetics, pharmacodynamics and side-effects of furosemide in neonates. The bibliographic search was performed using PubMed and EMBASE databases as search engines; January 2013 was the cutoff point. Furosemide half-life (t 1/2) is 6 to 20-fold longer, clearance (Cl) is 1.2 to 14-fold smaller and volume of distribution (Vd) is 1.3 to 6-fold larger than the adult values. t 1/2 shortens and Cl increases as the neonatal maturation proceeds. Continuous intravenous infusion of furosemide yields more controlled diuresis than the intermittent intravenous infusion. Furosemide may be administered by inhalation to infants with chronic lung disease to improve pulmonary mechanics. Furosemide stimulates prostaglandin E2 synthesis, a potent dilator of the patent ductus arteriosus, and the administration of furosemide to any preterm infants should be carefully weighed against the risk of precipitation of a symptomatic patent ductus arteriosus. Infants with low birthweight treated with chronic furosemide are at risk for the development of intra-renal calcifications.

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          The effect of intrauterine growth retardation on the development of renal nephrons.

          To investigate the effect of Type II (asymmetrical) intrauterine growth retardation (IUGR) on renal development. A prospective descriptive study. Department of Fetal and Infant Pathology, Liverpool Children's Hospital. Six (severely) affected IUGR stillbirths of known gestational age with a control group of stillbirths with birthweight greater than 10th centile, and eight liveborn IUGR infants who died within a year of birth with a control group of appropriately grown infants who died within a year of birth (postnatal groups). The kidneys from all the groups studied were analysed using unbiased, reproducible and objective design-based stereological techniques. Total renal nephron (glomerular) numbers and average volumes of total nephron and cortical and medullary nephron segments. Nephron number estimates lay below the control group's 5% prediction limit in five out of the six growth-retarded stillbirths, and were significantly (P less than 0.005, IUGR at 65% of the control mean) reduced in the postnatal group. Estimates of nephron (segment) volume did not differ between control and IUGR groups. Type II intrauterine growth retardation may exert a profound effect on renal development. The reduced nephron number at birth, together with the lack of any early postnatal compensation in either nephron number or nephron size, emphasizes the need for vigorous antenatal surveillance for IUGR and consideration of elective preterm delivery of affected fetuses. A systematic review of other organs, which develop in a similarly rapid fashion during the late intrauterine period, is indicated by this work. With one exception, all birthweights in the growth-retarded groups were below the third centile, thus the precise quantitative relation between progressive IUGR and renal function requires further assessment.
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            Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates.

            Extracorporeal membrane oxygenation (ECMO) is a prolonged form of cardiopulmonary bypass used to support patients with life-threatening respiratory or cardiac failure. In neonates, ECMO is used for a variety of indications, including sepsis and pulmonary diseases such as meconium aspiration syndrome, persistent pulmonary hypertension or congenital diaphragmatic hernia. In recent years, ECMO has been increasingly used after surgery to correct congenital cardiac defects. Despite the need for numerous drugs to maintain the ECMO circuit and treat the patient's underlying illness, relatively little is known of the disposition of drugs in this patient population. To date, the largest number of pharmacokinetic studies have been conducted with gentamicin and vancomycin. Both drugs have been found to have an increased volume of distribution, probably as a result of the addition of a large exogenous blood volume for circuit priming. Elimination half-lives for both drugs are prolonged during ECMO, with several studies demonstrating a return to expected values after decannulation. The reason for this prolonged elimination is probably multifactorial, with a reduction in renal function as the primary determinant. This same pattern of an increased volume of distribution and prolonged elimination has been found for several other drugs, including tobramycin, bumetanide and ranitidine. Other factors that affect drug disposition during ECMO include loss of the drug from adhesion to the circuit components and loss in the circulating blood volume during changes in the equipment. The benzodiazepines and propofol are largely sequestered within the circuit. Serum concentrations of heparin, morphine, fentanyl, furosemide, phenytoin and phenobarbital are also reduced by these mechanisms. The addition of haemofiltration or dialysis in up to a quarter of ECMO patients further complicates the determination of population pharmacokinetic parameters. The literature published to date on the pharmacokinetic changes associated with ECMO provide preliminary support for dosage adjustment; however, more research is needed to identify optimal administration strategies for this patient population.
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              Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis.

              Hemodynamic and neurohumoral responses to acute diuretic therapy were measured in 15 patients with severe chronic heart failure given intravenous furosemide, 1.3 +/- 0.6 (SD) mg/kg body weight. Left ventricular pump function deteriorated by 20 minutes, as indicated by a fall in stroke volume index (27 +/- 8 to 24 +/- 7 mL/min X m2 body surface area, p less than 0.01) and an increase in left ventricular filling pressure (28 +/- 7 to 33 +/- 9 mm Hg, p less than 0.01). Increases occurred in heart rate (87 +/- 13 to 91 +/- 16 beats/min, p less than 0.01), mean arterial pressure (90 +/- 15 to 96 +/- 15 mm Hg, p less than 0.01), systemic vascular resistance (1454 +/- 394 to 1676 +/- 415 dynes X s X cm-5, p less than 0.01), plasma renin activity (9.9 +/- 8.5 to 17.8 +/- 16 ng/mL X h, p less than 0.05), plasma norepinephrine level (667 +/- 390 to 839 +/- 368 pg/mL, p less than 0.01), and plasma arginine vasopressin level (6.2 +/- 1.3 to 8.3 +/- 2.0 pg/mL, p less than 0.01). During the next 3.5 hours the patients had diuresis (2085 +/- 1035 mL) and the expected fall in filling pressure (28 +/- 7 to 22 +/- 10 mm Hg, p less than 0.01). Neurohumoral indicators also returned toward the control levels. Intravenous furosemide, in patients with severe chronic heart failure, is associated with acute pump dysfunction temporally related to activation of the neurohumoral axis.
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                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                05 September 2013
                September 2013
                : 6
                : 9
                : 1094-1129
                Affiliations
                Section of Pharmacology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56100, Italy; E-Mail: pacifici@ 123456biomed.unipi.it ; Tel: +39-050-2218-721; Fax: +39-050-2218-717.
                Article
                pharmaceuticals-06-01094
                10.3390/ph6091094
                3818833
                24276421
                c68cbc83-4da4-433e-b2ea-8de15ec2568d
                © 2013 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 16 April 2013
                : 28 August 2013
                : 30 August 2013
                Categories
                Review

                furosemide,neonate,metabolism,pharmacokinetics,pharmacodynamics,continuous infusion,extracorporeal membrane oxygenation,side-effects

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