The efficiency concept in pharmacodynamics

The classic approach to describe the pharmacological response to a drug is to analyse its concentration-effect relationship, using a variety of possib le models such as maximum effect (E-max) models or sigmoid E-max models. Th e aim of this review is to discuss an alternative way of describing the pha rmacological effect in terms of effect per unit of drug concentration, inst ead of simple effect. This variable is called efficiency, analogous with co ncepts used in other fields. The pharmacodynamic model for efficiency is de rived from the sigmoid E-max model and is dependent on the same parameters. Since the sigmoid E-max model incorporates 'the law of diminishing returns' , requiring ever higher concentrations to increase the effect by a given pe rcentage, efficiency is bound to decrease with increasing concentrations. H owever, as a mathematical consequence of its derivation from the sigmoid E- max model, efficiency also has a maximum value, which can be expressed as a function of the slope factor (s) and drug concentration associated with ha lf the maximum effect (C-50), provided that the slope factor is greater tha n 1. The efficiency concept is potentially applicable to all drugs and particula rly useful for those that follow concentration-effect relationships accordi ng to E-max or sigmoid E-max models. Most experience has been obtained with loop diuretics, especially with furosemide (frusemide). Slow administratio n of furosemide, leading to slow excretion of the drug, has been shown, in many studies, to significantly increase the total diuretic effect per amoun t of drug recovered in In this review, some examples of the applicability of the efficiency concep t to other drugs, such as antibacterials, opioids and antineoplastics, are discussed. In addition to pharmacodynamically varying efficiency, other sat urable processes, such as the formation of active metabolites and saturable transport, may form a basis for the application of the efficiency concept. The efficiency of a drug dosage may also be influenced by tolerance and co unter-regulation produced by the drug. All these factors contribute to sche dule dependency. It is concluded that the shape of the time course of drug presentation to i ts site of action is an independent determinant of overall response. The po ssibility of adjusting the drug input profile to maximise therapeutic effec t per dose and to separate cumulated therapeutic from cumulated adverse eff ects should be considered in designing administration schedules and in drug development.