Optimization of the Therapeutic Index by Adjustment of the Rate of Drug Administration or Use of Drug Combinations: Exploratory Studies of Diuretics

Abstract

The purpose of this investigation was to explore theoretically certain strategies for optimizing the therapeutic index of drugs and to assess these strategies experimentally with two diuretics. Diuretic agents allow dosing rate flexibilities because the temporal profile of diuretic action can vary considerably as long as the total diuretic effect per day is the same. They can also be used in combination. Experiments were designed to determine if the therapeutic index of furosemide and hydrochlorothiazide can be optimized by administering one or the other at a certain rate or by administering the two drugs together in a certain ratio and at a certain rate. Male Lewis rats received one or the other drug, or combinations of the two, by i.v. infusion at different rates. Several timed urine collections were made under steady-state conditions, with excreted urine replaced volume for volume by i.v. lactated Ringer's solution. The urine flow rates and the urinary excretion rates of the diuretics and of Na⁺ and K⁺ were determined. The relationship between the diuretic effect of either of the two drugs given alone and the respective drug excretion rate could be described by the Hill equation. The ratio of urine flow rate to K⁺ excretion rate exhibited a marked dependence on hydrochlorothiazide excretion rate (highest ratio at high excretion rates), whereas the K⁺/Na⁺ excretion rate ratio was constant over a wide range of hydrochlorothiazide excretion rates. There was no significant change of these ratios with changing excretion rate of furosemide. Infusion of the two diuretics in combination of different ratios and at different combined rates under steady-state conditions revealed proportionality between the urinary excretion rates of Na⁺ and urine over a wide range and a decreasing K⁺ /urine excretion rate ratio with increasing urine flow rate. Hence, a favorable increase in the Na⁺/K⁺ excretion rate ratio was attained with increasing urine flow rate. These experiments and computer simulations demonstrate in principle the feasibility of optimizing the therapeutic index by appropriate selection of a drug's dosing rate or by dosing a combination of two drugs at an appropriate ratio and rate.