Furosemide dosage input : consequences for diuretic effect, tolerance and efficiency

Abstract: Furosemide dosage input - consequences for diuretic effect,tolerance and efficiency By Monique Wakelkamp, Division of Clinical Pharmacology,Department of Medical Laboratory Sciences & Technology,Karolinska Institute, Huddinge University Hospital, S- 141 86Stockholm, Sweden. The development of new dosage forms raises the question of how thepharmacokinetic pharmacodynamic (PK-PD) profile of a drug isinfluenced by the drug input rate. Furosemide was used as a modeldrug to study the relationship between drug input rate and effect.The PK- PD relationship of furosemide is nonlinear and subject tocounter-clockwise hysteresis and tolerance development. The diureticeffect is a function of the urinary excretion rate of the drug, whichenables frequent simultaneous sampling of stimulus and effect. Thesecharacteristics make furosemide an interesting tool drug for PK-PDmodeling. The findings should have general applicability, sinceknowledge and methodology to study the time course of drug effects inrelation to dose, dosage form and drug concentration form the basisof a rational therapeutic strategy. The administration of three 30 mg furosemide doses as rapidinfusions gave rise to profound tolerance development, that was moremarked for sodium excretion than for diuresis. An indirect-responsemodel including an additional modifier was applied to describe thedecrease in diuretic and natriuretic response. Physiologiccounter-action was shown as a significant increase in plasma activerenin and a decrease in atrial natriuretic peptide levels, togetherwith the development of a negative sodium balance. The relationshipbetween tolerance development and drug input rate was investigated byadministration of a 10 mg furosemide dose using four differentinfusion rates. Tolerance developed for all treatments, but the timecourse of tolerance development and the shape of the excretion rate -response curve were highly dependent on the infusion rate. A slowinput of the drug was found to delay and blunt the development oftolerance, although it was easier to observe from the graphs asclockwise hysteresis. Furosemide is subject to absorption-limitedkinetics. This was further investigated by studying the effect offood on the bioavailability, effect and efficiency of two controlledrelease formulations of 60 mg furosemide. The efficiency concept wasapplied to show the influence of the furosemide absorption rate onthe total diuretic response. Probenecid inhibits the tubularsecretion of furosemide and this may profoundly influence the timecourse of efficiency of the drug and therefore account fordifferences in effect. This hypothesis was investigated byadministering 30 mg of furosemide as a bolus dose, a slow-rateinfusion and a bolus dose combined with probenecid. It was shown thatthe time course of the natriuretic effect was very similar for thelatter two treatments and that total natriuretic efficiency wassignificantly higher compared to the bolus dose. The increase inefficiency offers an explanatory mechanism by which pretreatment withprobenecid increases the total diuretic response. The time of maximumresponse to furosemide was studied after different dose sizes andfound to increase with dose. This finding was used for modelselection and validation, as the increase in the time of maximumdiuretic and natriuretic response was better predicted by theindirect-response model than the effect-compartment model, whichassumes the time of maximum response to be dose independent. Duringextensive data processing, it was found that the final results ofPK-PD modeling may be different, depending on the numericalperformance of the computer processor. This further illustrates theneed for quality assurance and validation for these procedures. Keywords: furosemide, drug input rate, pharmacokinetics,pharmacodynamics, tolerance, efficiency, probenecid ISBN 91-628-2612-3