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

The development of new dosage forms raises the question of how the pharmacokinetic pharmacodynamic (PK-PD) profile of a drug is influenced by the drug input rate. Furosemide was used as a model drug to study the relationship between drug input rate and effect. The PK- PD relationship of furosemide is nonlinear and subject to counter-clockwise hysteresis and tolerance development. The diuretic effect is a function of the urinary excretion rate of the drug, which enables frequent simultaneous sampling of stimulus and effect. These characteristics make furosemide an interesting tool drug for PK-PD modeling. The findings should have general applicability, since knowledge and methodology to study the time course of drug effects in relation to dose, dosage form and drug concentration form the basis of a rational therapeutic strategy.

The administration of three 30 mg furosemide doses as rapid infusions gave rise to profound tolerance development, that was more marked for sodium excretion than for diuresis. An indirect-response model including an additional modifier was applied to describe the decrease in diuretic and natriuretic response. Physiologic counter-action was shown as a significant increase in plasma active renin and a decrease in atrial natriuretic peptide levels, together with the development of a negative sodium balance. The relationship between tolerance development and drug input rate was investigated by administration of a 10 mg furosemide dose using four different infusion rates. Tolerance developed for all treatments, but the time course of tolerance development and the shape of the excretion rate -response curve were highly dependent on the infusion rate.

A slow input of the drug was found to delay and blunt the development of tolerance, although it was easier to observe from the graphs as clockwise hysteresis. Furosemide is subject to absorption-limited kinetics. This was further investigated by studying the effect of food on the bioavailability, effect and efficiency of two controlled release formulations of 60 mg furosemide. The efficiency concept was applied to show the influence of the furosemide absorption rate on the total diuretic response. Probenecid inhibits the tubular secretion of furosemide and this may profoundly influence the time course of efficiency of the drug and therefore account for differences in effect. This hypothesis was investigated by administering 30 mg of furosemide as a bolus dose, a slow-rate infusion and a bolus dose combined with probenecid. It was shown that the time course of the natriuretic effect was very similar for the latter two treatments and that total natriuretic efficiency was significantly higher compared to the bolus dose.

The increase inefficiency offers an explanatory mechanism by which pretreatment with probenecid increases the total diuretic response. The time of maximum response to furosemide was studied after different dose sizes and found to increase with dose. This finding was used for model selection and validation, as the increase in the time of maximum diuretic and natriuretic response was better predicted by the indirect-response model than the effect-compartment model, which assumes the time of maximum response to be dose independent. During extensive data processing, it was found that the final results of PK-PD modeling may be different, depending on the numerical performance of the computer processor. This further illustrates the need for quality assurance and validation for these procedures.