Pharmacokinetic Changes in Patients With Oedema

Abstract

The pharmacokinetics of furosemide (frusemide) in patients with oedema have been relatively well studied, but in many studies it is unclear whether the disease or the oedema per se has the major effect. The rate of absorption of oral furosemide in patients with oedema was decreased, but total bioavailability was almost unchanged. The peak serum concentration (Cmax) and time taken to achieve Cmax were either decreased or unchanged. Binding of furosemide to plasma proteins is lower in patients with congestive heart failure (CHF), decompensated liver cirrhosis (DLC) and nephrotic syndrome, probably as a result of hypoalbuminaemia. The elimination half-life (t1/2) can be unchanged (CHF, DLC) or prolonged (chronic renal failure: CRF). Plasma and renal clearance are reduced in patients with CRF and nephrotic syndrome, but are almost unchanged in CHF and DLC. Disease-induced disorders are mainly responsible for the alterations of furosemide pharmacokinetics in oedematous conditions, while the influence of oedema per se is probably not clinically relevant. The pharmacokinetics of digoxin have been studied in a small number of studies only. In patients with CHF, considerable interindividual differences have been found. Because digoxin has a narrow therapeutic window, this drug should be administered cautiously to oedematous patients. Theophylline has higher bioavailability in patients with oedema, with a significantly higher Cmax in patients with hepatic cirrhosis and CHF than in healthy volunteers (29 and 22%, respectively). Furthermore, clearance decreases and t1/2 increases in these patients. Angiotensin converting enzyme (ACE) inhibitors are often administered as prodrugs, and their pharmacokinetic profile could be influenced by the diseases that accompany oedematous states. However, the effect of oedema is difficult to discriminate from that of the disease. Individual ACE inhibitors are affected differently, but importantly the dosage of perindopril should be reduced in patients with CHF, while for most other ACE inhibitors the changes in pharmacokinetic parameters are clinically irrelevant. In conclusion, studies on pharmacokinetic changes in oedema are limited. Besides affecting absorption (after oral administration) and conversion of the prodrug to the active form, probably as a result of the associated disease, oedema has not been proven to cause any clinically relevant changes in pharmacokinetic parameters for individual drugs. However, further studies of this aspect of pharmacokinetics are needed.

Increased cyclosporine bioavailability induced by experimental nephrotic syndrome in rats

“…However, no comparison was carried out with a suitable control group and thus no information on the actual pharmacokinetic alterations was provided (Moulin et al 1989). Edema, hypoproteinemia, and hypercholesterolemia are expected to change the bioavailability of the drug via the alterations in protein-binding and clearance (Gugler et al 1975;Rane et al 1978;Vrhovac et al 1995). Nozu et al (2005) reported that 33% of pediatric nephrotic patients present a late peak absorption and discourage the use of C2 as monitoring tool in this population.…”

Decreased cyclosporine exposure during the remission of nephrotic syndrome

“…These findings give the rational for a higher CsA dose for remission induction and a lower dose once the patient has achieved remission. CsA ng/mL CsA ng/mL Patients with the remission of NS also showed a statistically significant lower t max , which could be related to a better intestinal absorption once the patient is in relapse, since the nephrotic state is related to intestinal edema and malabsorption [22]. It is important to notice that, even when the trough levels were lower at 24 weeks of treatment, they do not reflect the real CsA exposure and were the only pharmacokinetic parameter without improvement of the interindividual coefficient of variation after 24 weeks of treatment.…”

“…In addition to these age-related factors, it is possible that NS may alter drug disposition. Notwithstanding, studies on NS-induced pharmacokinetic alterations are scarce, despite that the presence of edema, hypoproteinemia, and hypercholesterolemia allow anticipating changes in drug bioavailability [21,22]. Hypercholesterolemia is particularly important in CsA pharmacokinetics; since the drug is highly lipophilic [23], it binds to blood cells and plasma proteins, and the relative distribution depends on temperature, drug concentration, hematocrit, and plasma lipoproteins [24].…”

Bioequivalence evaluation of two brands of furosemide 40mg tablets (Salurin and Lasix) in healthy human volunteers

“…The rate and extent of absorption are complicated by a large degree of intersubject and intrasubject variabilities [5,6,[8][9][10][11]. The rate of absorption may be decreased in patients with oedema but the total bioavailability remains unchanged [12]. The onset of diuresis following oral administration is within 1 h, and the peak effect occurs within the first or second hour with a duration that lasts 6-8 h [8,12,13].…”

“…The rate of absorption may be decreased in patients with oedema but the total bioavailability remains unchanged [12]. The onset of diuresis following oral administration is within 1 h, and the peak effect occurs within the first or second hour with a duration that lasts 6-8 h [8,12,13]. Furosemide is extensively bound to plasma proteins, mainly to albumin, plasma concentrations ranging from 1 to 400 mg/ml are 91% to 99% bound in healthy individuals while the unbound fraction averages 2.3% to 4.1% at therapeutic concentrations [8,10,11,13].…”